CBL

Summary

CBL (Cbl proto-oncogene, HGNC:1541) is a protein-coding gene on chromosome 11q23.3, encoding E3 ubiquitin-protein ligase CBL (P22681). E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors.

This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5’ UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder.

Source: NCBI Gene 867 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CBL-related disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 22
• Clinical variants (ClinVar): 2,431 total — 12 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 143
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 3 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005188

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1541
Approved symbol	CBL
Name	Cbl proto-oncogene
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	RNF55, c-Cbl
Ensembl gene	ENSG00000110395
Ensembl biotype	protein_coding
OMIM	165360
Entrez	867

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 nonsense_mediated_decay

ENST00000264033, ENST00000634301, ENST00000634586, ENST00000634840, ENST00000637974, ENST00000700472

RefSeq mRNA: 1 — MANE Select: NM_005188 NM_005188

CCDS: CCDS8418

Canonical transcript exons

ENST00000264033 — 16 exons

Exon	Start	End
ENSE00000796209	119284969	119285100
ENSE00000796211	119287852	119287946
ENSE00000796212	119296918	119297034
ENSE00000796213	119297384	119297481
ENSE00000796214	119298358	119298540
ENSE00001128273	119278510	119278713
ENSE00001128289	119277757	119277844
ENSE00001206751	119285189	119285566
ENSE00001238481	119299495	119308149
ENSE00001240776	119275997	119276134
ENSE00001240782	119274832	119274953
ENSE00001240790	119273868	119274024
ENSE00001240795	119271735	119271881
ENSE00001240799	119232448	119232695
ENSE00001240819	119206339	119206612
ENSE00001795866	119278166	119278297

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 93.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.1189 / max 461.1191, expressed in 1794 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117108	9.2272	1757
117105	4.5980	1473
117107	2.0791	1203
117106	0.2146	56

Top tissues by expression

297 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.28	gold quality
trigeminal ganglion	UBERON:0001675	91.77	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.74	gold quality
trabecular bone tissue	UBERON:0002483	91.00	gold quality
saphenous vein	UBERON:0007318	89.97	gold quality
dorsal root ganglion	UBERON:0000044	89.80	gold quality
superficial temporal artery	UBERON:0001614	89.66	gold quality
nipple	UBERON:0002030	89.52	gold quality
blood	UBERON:0000178	89.41	gold quality
visceral pleura	UBERON:0002401	89.14	gold quality
gingival epithelium	UBERON:0001949	88.95	gold quality
ventricular zone	UBERON:0003053	88.70	gold quality
superior vestibular nucleus	UBERON:0007227	88.70	gold quality
medial globus pallidus	UBERON:0002477	88.68	gold quality
inferior vagus X ganglion	UBERON:0005363	88.63	gold quality
subthalamic nucleus	UBERON:0001906	88.48	gold quality
lower lobe of lung	UBERON:0008949	88.37	gold quality
adult organism	UBERON:0007023	88.08	gold quality
globus pallidus	UBERON:0001875	87.93	gold quality
pylorus	UBERON:0001166	87.77	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.74	gold quality
monocyte	CL:0000576	87.68	gold quality
cardia of stomach	UBERON:0001162	87.53	gold quality
ventral tegmental area	UBERON:0002691	87.52	gold quality
leukocyte	CL:0000738	87.37	gold quality
mononuclear cell	CL:0000842	87.33	gold quality
parietal pleura	UBERON:0002400	87.04	gold quality
substantia nigra pars compacta	UBERON:0001965	86.95	gold quality
gingiva	UBERON:0001828	86.92	gold quality
synovial joint	UBERON:0002217	86.88	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR2, STAT2

miRNA regulators (miRDB)

413 targeting CBL, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-616-5P	99.98	75.58	4775

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• novel E3 ubiquitin-protein ligase; role in regulation of immune response - review (PMID:11826757)
• Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors (PMID:11894095)
• The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met (PMID:11894096)
• Negative regulation of Lck by Cbl ubiquitin ligase (PMID:11904433)
• Cbl-b protein and CIN85 downregulate receptor tyrosine kinases (PMID:12177062)
• Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors. (PMID:12218189)
• complexation with ArgBP2 mediates ubiquitination and degradation of c-Abl (PMID:12475393)
• c-Cbl-dependent EphA2 protein degradation is induced by ligand binding. (PMID:12496371)
• MLL-CBL fusion was the result of an interstitial deletion in patients with de novo acute myeloid leukemia (FAB-M1). (PMID:12696071)
• Ron tyrosine kinase receptor desensitization mediated by c-Cbl and its binding partner Grb2. (PMID:12802274)
• c-cbl binds to hSpry2, and this interaction is critical for its physiological function in a signal-specific context (PMID:12815057)
• Cbl has a role, via its ubiquitin ligase activity, as a negative regulator of activated Vav (PMID:12881521)
• Lower expression of cbl is associated with acute myeloid leukemia-M2 and higher expression of cbl is associated with acute myeloid leukemia-M5 (PMID:14738146)
• the c-Cbl/CD2AP complex binds to activated Flt-1 and plays a crucial role in its endocytosis and subsequent degradation. (PMID:15001553)
• Recruitment of CBL to lipid rafts mediates signals important for actin reorganization in growing neurites. (PMID:15128873)
• Sts-1 and Sts-2 bind to Cbl and inhibit endocytosis of receptor tyrosine kinases (PMID:15159412)
• CBL has a role in down-regulation of Lyn and Fyn in osteoblast differentiation induced by constitutive FGFR2 activation (PMID:15190072)
• c-Cbl has a role in EGFR trafficking (PMID:15210722)
• Differences in ubiquitin-binding may reflect distinct regulatory functions of c-Cbl and Cbl-b. (PMID:15273720)
• c-Cbl-dependent ubiquitination of p75NTR involved in the regulation of p75NTR signalling. (PMID:15337528)
• c-Cbl guides the epidermal growth factor receptor into clathrin-coated pits by two distinct modes of Eps15 recruitment (PMID:15465819)
• Grb2-mediated recruitment of the functional RING domain of Cbl to the EGFR is essential and sufficient to support receptor endocytosis (PMID:15635092)
• mediates ubiquitination and lysosomal degradation of PAR(2) to irrevocably terminate its signaling (PMID:15708858)
• the alpha5 integrin subunit has a role in the induction of apoptosis triggered by FGFR2 activation in osteoblasts, and a Cbl-dependent mechanism is involved in the coordinated regulation of cell apoptosis induced by alpha5 integrin degradation (PMID:15728256)
• Data show that infected cell protein 0 (ICP0) binds CIN85 in a reciprocal manner and that the complexes pulled down by ICP0 also contain Cbl. (PMID:15824310)
• dynamin, Cbl, and Src coordinately participate in signaling complexes that are important in the assembly and remodeling of the actin cytoskeleton, leading to changes in osteoclast adhesion, migration, and resorption (PMID:15872089)
• Results suggest a novel function for c-Cbl, microtubule binding and stabilization. (PMID:15878338)
• Cbl promotes clustering of endocytic adaptor proteins. (PMID:16228008)
• EGF-R fate is controlled by a checkpoint downstream of receptor ubiquitination whose regulation by the Cbl RF tail may require Sprouty2 degradation. (PMID:16246327)
• CD21 activation triggered Cbl tyrosine phosphorylation, which interacts with SH2 domains of p85 subunit, SH2 domains of Crk-L and with tyrosine phosphorylated Syk kinase. CD21 activation triggers dissociation of Cbl-Vav complex. (PMID:16289966)
• the SH3 domain of betaPix specifically interacts with a proline-arginine motif (PxxxPR) present within the ubiquitin ligase Cbl and Pak1 kinase. Cbl and Pak1 compete for binding to betaPix. (PMID:16407834)
• results implicate CD45, Cbl, Cbl-b, src kinases and potentially other associated proteins as mediators of SDF-1alpha/CXCL12-induced cell migration of Jurkat T cells (PMID:16503409)
• ubiquitin ligase of EGFR, namely c-Cbl, also mediates receptor modification with the ubiquitin-like molecule Nedd8 (PMID:16735510)
• By lysing primary hemopoietic cells at high pH, BCR-ABL1 protein-degradative activity was inhibited & association between BCR-ABL1 protein in complexes with adaptor proteins CBL, CRKL & GRB2 in primary chronic myeloid leukaemia material was demonstrated (PMID:16955467)
• Twist haploinsufficiency results in decreased Cbl-mediated PI3K degradation in osteoblasts. (PMID:17003487)
• Alix inhibits down-regulation of PDGFRbeta by modulating the interaction between c-Cbl and the receptor, thereby affecting the ubiquitination of the receptor (PMID:17082185)
• Depletion of Cbl and Cbl-b E3 ubiquitin ligases by RNA interference, or overexpression of a Cbl dominant inhibitory mutant (Cbl-N), inhibited Spred-2 ubiquitination. (PMID:17094949)
• The interaction between c-Cbl and SLAP in v-Abl-3T3 cells positively influenced c-Cbl-mediated spreading and adhesion of these cells (PMID:17237826)
• corecruitment of c-Cbl and PLCgamma1 to VEGFR-2 serves as a mechanism to fine-tune the angiogenic signal relay of VEGFR-2 (PMID:17372230)
• novel mutations in c-CBL and CBL-b have been identified in human acute myeloid leukemia (PMID:17475912)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cbl	ENSDARG00000009958
mus_musculus	Cbl	ENSMUSG00000034342
rattus_norvegicus	Cbl	ENSRNOG00000008444

Paralogs (2): CBLB (ENSG00000114423), CBLC (ENSG00000142273)

Protein

Protein identifiers

E3 ubiquitin-protein ligase CBL — P22681 (reviewed: P22681)

Alternative names: Casitas B-lineage lymphoma proto-oncogene, Proto-oncogene c-Cbl, RING finger protein 55, RING-type E3 ubiquitin transferase CBL, Signal transduction protein CBL

All UniProt accessions (6): P22681, A0A0U1RQX8, A0A0U1RR39, A0A0U1RRJ5, A0A1B0GW38, A0A8V8TQA9

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, CSF1R, EPHA8 and KDR and mediates their ubiquitination to terminate signaling. Recognizes membrane-bound HCK, SRC and other kinases of the SRC family and mediates their ubiquitination and degradation. Ubiquitinates EGFR and SPRY2. Involved in LAG3-mediated inhibition of TCR signaling: following ligand-binding to LAG3, catalyzes ‘Lys-63’-linked ubiquitination of LAG3, unleashing the LAG3 C-terminus from the membrane, and initiating a signaling that prevents TCR activation. Ubiquitinates NECTIN1 following association between NECTIN1 and herpes simplex virus 1/HHV-1 envelope glycoprotein D, leading to NECTIN1 removal from cell surface. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The ‘Tyr-731’ phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. In association with CBLB, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA.

Subunit / interactions. Forms homodimers; IFT20 promotes the formation of stable homodimers. Interacts (phosphorylated at Tyr-731) with PIK3R1. Associates with NCK via its SH3 domain. The phosphorylated C-terminus interacts with CD2AP via its second SH3 domain. Binds to UBE2L3. Interacts with adapters SLA, SLA2 and with the phosphorylated C-terminus of SH2B2. Interacts with EGFR, SYK and ZAP70 via the highly conserved Cbl-N region. Also interacts with SORBS1 and INPPL1/SHIP2. Interacts with phosphorylated LAT2. Interacts with CBLB. Interacts with ALK, AXL, BLK, FGR and FGFR2. Interacts with CSF1R, EPHB1, FLT1, KDR, PDGFRA and PDGFRB; regulates receptor degradation through ubiquitination. Interacts with HCK and LYN. Interacts with ATX2. Interacts with TEK/TIE2 (tyrosine phosphorylated). Interacts with SH3KBP1 and this interaction is inhibited in the presence of SHKBP1 or ARAP1. Interacts with SIGLEC10. Interacts with IFT20. Interacts with SPRY2; the interaction inhibits CBL-mediated ubiquitination of EGFR. Interacts (phosphorylated at Tyr-774) with tensin TNS4 (via SH2 domain); the interaction is enhanced in the presence of EGF and reduces interaction of CBL with EGFR. Interacts with EGFR; the interaction is reduced in the presence of TNS4. Interacts with CD5. Interacts with CD93. (Microbial infection) Interacts with M.tuberculosis LpqN, which influences the balance between intrinsic antibacterial and antiviral defense.

Subcellular location. Cytoplasm. Cell membrane. Cell projection. Cilium. Golgi apparatus.

Post-translational modifications. Phosphorylated on tyrosine residues by ALK, EGFR, SYK, FYN and ZAP70. Phosphorylated on tyrosine residues in response to FLT1 and KIT signaling. Phosphorylated on tyrosine residues by INSR and FGR. Phosphorylated on several tyrosine residues by constitutively activated FGFR3. Not phosphorylated at Tyr-731 by FGFR3. Phosphorylated on tyrosine residues by activated CSF1R, PDGFRA and PDGFRB. Phosphorylated on tyrosine residues by HCK. Ubiquitinated, leading to its degradation via the proteasome. Ubiquitination is negatively regulated by IFT20.

Disease relevance. Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) [MIM:613563] A syndrome characterized by a phenotype reminiscent of Noonan syndrome. Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects. Some have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme. The N-terminus is composed of the phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. This protein has one functional calcium-binding site.

RefSeq proteins (1): NP_005179* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR003153	Adaptor_Cbl_N_hlx	Domain
IPR009060	UBA-like_sf	Homologous_superfamily
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR014741	Adaptor_Cbl_EF_hand-like	Domain
IPR014742	Adaptor_Cbl_SH2-like	Domain
IPR015940	UBA	Domain
IPR017907	Znf_RING_CS	Conserved_site
IPR018957	Znf_C3HC4_RING-type	Domain
IPR024159	Cbl_PTB	Domain
IPR024162	Adaptor_Cbl	Family
IPR036537	Adaptor_Cbl_N_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily

Pfam: PF00097, PF00627, PF02262, PF02761, PF02762

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (113 total): helix 24, strand 17, region of interest 14, modified residue 13, mutagenesis site 12, sequence variant 11, turn 6, binding site 6, compositionally biased region 5, domain 2, chain 1, zinc finger region 1, sequence conflict 1

Structure

Experimental structures (PDB)

33 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3BUX	X-RAY DIFFRACTION	1.35
3BUW	X-RAY DIFFRACTION	1.45
7SIY	X-RAY DIFFRACTION	1.48
5HKY	X-RAY DIFFRACTION	1.8
5HKZ	X-RAY DIFFRACTION	1.8
5HKX	X-RAY DIFFRACTION	1.85
3PLF	X-RAY DIFFRACTION	1.92
2Y1N	X-RAY DIFFRACTION	2
3BUM	X-RAY DIFFRACTION	2
3BUN	X-RAY DIFFRACTION	2
9ERZ	X-RAY DIFFRACTION	2.02
1YVH	X-RAY DIFFRACTION	2.05
2CBL	X-RAY DIFFRACTION	2.1
2OO9	X-RAY DIFFRACTION	2.1
3OB2	X-RAY DIFFRACTION	2.1
1B47	X-RAY DIFFRACTION	2.2
3OB1	X-RAY DIFFRACTION	2.2
5HL0	X-RAY DIFFRACTION	2.2
4A49	X-RAY DIFFRACTION	2.21
5HKW	X-RAY DIFFRACTION	2.25
5O76	X-RAY DIFFRACTION	2.47
6XAR	X-RAY DIFFRACTION	2.5
3BUO	X-RAY DIFFRACTION	2.6
2Y1M	X-RAY DIFFRACTION	2.67
4A4C	X-RAY DIFFRACTION	2.7
4A4B	X-RAY DIFFRACTION	2.79
5J3X	X-RAY DIFFRACTION	2.82
1FBV	X-RAY DIFFRACTION	2.9
6O02	X-RAY DIFFRACTION	2.95
4GPL	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22681-F1	64.27	0.36

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (6): 229; 231; 233; 235; 240; 294

Post-translational modifications (13): 371, 439, 452, 483, 619, 642, 668, 669, 674, 700, 731, 774, 900

Mutagenesis-validated functional residues (12):

Position	Phenotype
80	abolishes interaction with zap70.
82	abolishes interaction with zap70.
229	abolishes interaction with zap70.
240	abolishes interaction with zap70.
294	abolishes interaction with zap70.
306	abolishes interaction with zap70 and ephb1, but does not affect interaction with sla. reduces ubiquitination and therefo
371	strongly reduces tyrosine phosphorylation by insr; when associated with f-700 and f-774.
381	loss of ubiquitin ligase activity.
674	does not affect interaction with tns4 following egf stimulation.
700	does not affect interaction with tns4 following egf stimulation. strongly reduces tyrosine phosphorylation by insr; when
731	no effect on tyrosine phosphorylation by insr. loss of phosphorylation by src. inhibition of bone resorption. abolishes
774	loss of interaction with tns4 following egf stimulation. strongly reduces tyrosine phosphorylation by insr; when associa

Function

Pathways and Gene Ontology

Reactome pathways

51 pathways

ID	Pathway
R-HSA-1059683	Interleukin-6 signaling
R-HSA-1236382	Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
R-HSA-1295596	Spry regulation of FGF signaling
R-HSA-1433559	Regulation of KIT signaling
R-HSA-182971	EGFR downregulation
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-5637810	Constitutive Signaling by EGFRvIII
R-HSA-5654726	Negative regulation of FGFR1 signaling
R-HSA-5654727	Negative regulation of FGFR2 signaling
R-HSA-5654732	Negative regulation of FGFR3 signaling
R-HSA-5654733	Negative regulation of FGFR4 signaling
R-HSA-6807004	Negative regulation of MET activity
R-HSA-8849469	PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8875360	InlB-mediated entry of Listeria monocytogenes into host cell
R-HSA-912631	Regulation of signaling by CBL
R-HSA-9680350	Signaling by CSF1 (M-CSF) in myeloid cells
R-HSA-9706369	Negative regulation of FLT3
R-HSA-9706377	FLT3 signaling by CBL mutants
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-1643713	Signaling by EGFR in Cancer
R-HSA-168256	Immune System
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-177929	Signaling by EGFR
R-HSA-190236	Signaling by FGFR
R-HSA-199991	Membrane Trafficking

MSigDB gene sets: 763 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_PLATELET_DERIVED_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GGGACCA_MIR133A_MIR133B, GOBP_REGULATION_OF_CELL_ACTIVATION, AGGAAGC_MIR5163P, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, REACTOME_INTERLEUKIN_6_SIGNALING, GOBP_RESPONSE_TO_ETHANOL, GOBP_RESPONSE_TO_IONIZING_RADIATION, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (34): ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), DNA damage response (GO:0006974), signal transduction (GO:0007165), male gonad development (GO:0008584), response to gamma radiation (GO:0010332), response to activity (GO:0014823), protein ubiquitination (GO:0016567), cytokine-mediated signaling pathway (GO:0019221), regulation of Rap protein signal transduction (GO:0032487), response to testosterone (GO:0033574), cellular response to platelet-derived growth factor stimulus (GO:0036120), negative regulation of epidermal growth factor receptor signaling pathway (GO:0042059), response to starvation (GO:0042594), negative regulation of apoptotic process (GO:0043066), mast cell degranulation (GO:0043303), response to ethanol (GO:0045471), positive regulation of epidermal growth factor receptor signaling pathway (GO:0045742), symbiont entry into host cell (GO:0046718), positive regulation of receptor-mediated endocytosis (GO:0048260), protein stabilization (GO:0050821), negative regulation of T cell receptor signaling pathway (GO:0050860), negative regulation of T cell activation (GO:0050868), protein autoubiquitination (GO:0051865), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), ubiquitin-dependent endocytosis (GO:0070086), protein K63-linked ubiquitination (GO:0070534), cellular response to hypoxia (GO:0071456), cellular response to nerve growth factor stimulus (GO:1990090), regulation of platelet-derived growth factor receptor-alpha signaling pathway (GO:2000583), protein polyubiquitination (GO:0000209), cell surface receptor signaling pathway (GO:0007166), regulation of signaling (GO:0023051), regulation of intracellular signal transduction (GO:1902531)

GO Molecular Function (15): phosphotyrosine residue binding (GO:0001784), ubiquitin-protein transferase activity (GO:0004842), calcium ion binding (GO:0005509), zinc ion binding (GO:0008270), SH3 domain binding (GO:0017124), receptor tyrosine kinase binding (GO:0030971), phosphatidylinositol 3-kinase regulatory subunit binding (GO:0036312), cadherin binding (GO:0045296), ephrin receptor binding (GO:0046875), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), protein kinase binding (GO:0019901), metal ion binding (GO:0046872), protein tyrosine kinase binding (GO:1990782)

GO Cellular Component (14): Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cilium (GO:0005929), flotillin complex (GO:0016600), growth cone (GO:0030426), membrane raft (GO:0045121), perinuclear region of cytoplasm (GO:0048471), sperm end piece (GO:0097229), cytoplasm (GO:0005737), membrane (GO:0016020), axon (GO:0030424), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-23 pathways:

Category	Pathways
Interleukin-6 family signaling	1
Signaling by Ligand-Responsive EGFR Variants in Cancer	1
Negative regulation of FGFR1 signaling	1
Negative regulation of FGFR2 signaling	1
Negative regulation of FGFR3 signaling	1
Negative regulation of FGFR4 signaling	1
Signaling by SCF-KIT	1
Signaling by EGFR	1
Signaling by TGF-beta Receptor Complex	1
Signaling by EGFRvIII in Cancer	1
Signaling by FGFR1	1
Signaling by FGFR2	1
Signaling by FGFR3	1
Signaling by FGFR4	1
Signaling by MET	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
protein ubiquitination	2
epidermal growth factor receptor signaling pathway	2
regulation of epidermal growth factor receptor signaling pathway	2
signaling receptor binding	2
modification-dependent protein catabolic process	1
cellular response to stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
gonad development	1
development of primary male sexual characteristics	1
response to ionizing radiation	1
response to stimulus	1
protein modification by small protein conjugation	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
Rap protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
response to lipid	1
response to ketone	1
response to platelet-derived growth factor	1
cellular response to growth factor stimulus	1
negative regulation of ERBB signaling pathway	1
response to stress	1
response to nutrient levels	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
mast cell activation involved in immune response	1
mast cell mediated immunity	1
lysosome localization	1
leukocyte degranulation	1
establishment of organelle localization	1
response to alcohol	1
positive regulation of ERBB signaling pathway	1
viral life cycle	1

Protein interactions and networks

STRING

2650 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CBL	GRB2	P29354	996
CBL	SH3KBP1	Q96B97	996
CBL	EGFR	P00533	995
CBL	SRC	P12931	993
CBL	CRKL	P46109	993
CBL	CRK	P46108	992
CBL	RAPGEF1	Q13905	987
CBL	ZAP70	P43403	975
CBL	FYN	P06241	961
CBL	SHC1	P29353	940
CBL	LCP2	Q13094	931
CBL	SORBS1	Q9BX66	930
CBL	SYK	P43405	926
CBL	TCN1	P20061	911
CBL	CD2AP	Q9Y5K6	910

IntAct

444 interactions, top by confidence:

A	B	Type	Score
CBL	SH3KBP1	psi-mi:“MI:0915”(physical association)	0.980
SH3KBP1	CBL	psi-mi:“MI:0915”(physical association)	0.980
SH3KBP1	CBL	psi-mi:“MI:0914”(association)	0.980
CBL	GRB2	psi-mi:“MI:0915”(physical association)	0.960
GRB2	CBL	psi-mi:“MI:0915”(physical association)	0.960
EGFR	CBL	psi-mi:“MI:0915”(physical association)	0.960
CBL	EGFR	psi-mi:“MI:0915”(physical association)	0.960
CBL	EGFR	psi-mi:“MI:0407”(direct interaction)	0.960
PIK3R1	CBL	psi-mi:“MI:0915”(physical association)	0.940
CBL	PIK3R1	psi-mi:“MI:0915”(physical association)	0.940
NPHP1	NPHP4	psi-mi:“MI:2364”(proximity)	0.930
CBL	CRK	psi-mi:“MI:0915”(physical association)	0.920
CRK	CBL	psi-mi:“MI:0915”(physical association)	0.920
CRKL	CBL	psi-mi:“MI:0915”(physical association)	0.870
CBL	MET	psi-mi:“MI:2364”(proximity)	0.860
CBL	SPRY2	psi-mi:“MI:0914”(association)	0.860
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
CBL	CD2AP	psi-mi:“MI:0915”(physical association)	0.800
CBL	YWHAE	psi-mi:“MI:0915”(physical association)	0.770
GRB2	WIPF3	psi-mi:“MI:0914”(association)	0.730

BioGRID (1481): CBL (Affinity Capture-Western), CBL (Affinity Capture-Western), SIRT2 (Affinity Capture-Western), CBL (Affinity Capture-Western), ABL1 (Biochemical Activity), BCR (Biochemical Activity), CBL (Affinity Capture-Western), CBL (Reconstituted Complex), CBL (Affinity Capture-Western), CBL (Reconstituted Complex), CBL (Affinity Capture-Western), TGFBR2 (Biochemical Activity), UBE2M (Reconstituted Complex), UBC (Co-crystal Structure), EGFR (Biochemical Activity)

ESM2 similar proteins: A1YFY6, A2T6X9, A6H7I8, B2RUJ5, F1M5F3, F1N2W9, O35430, O35431, O95487, O95628, O95644, P0C6S7, P14316, P17863, P22681, P22682, P23798, P23906, P35227, P81133, P98084, Q02410, Q0IHY4, Q13469, Q14190, Q14432, Q1L994, Q3UR85, Q52L14, Q5CD77, Q5RD33, Q60591, Q61045, Q61079, Q66JB6, Q69ZT9, Q6NRE7, Q6QB00, Q8BIZ1, Q8BT14

Diamond homologs: G3V8H4, P22681, P22682, P23092, Q13191, Q3TTA7, Q6DFR2, Q6GQL0, Q6NRE7, Q80XL1, Q8K4S7, Q9ULV8, A0A1L8FG46, A0A1L8FM16, B1AUE5, C0HBT3, C0HKD7, D2H0Y8, E1B7X3, O60683, O64425, P87176, P93030, Q09463, Q1ACD5, Q28GL3, Q2PFU6, Q3T139, Q3UF64, Q587N7, Q5C8U1, Q5C8U3, Q5C8U4, Q5D7H8, Q5D7I2, Q5D7I3, Q5D7I5, Q5D7J2, Q5M7Z0, Q5REL3

SIGNOR signaling

58 interactions.

A	Effect	B	Mechanism
CBL	down-regulates	INSR	ubiquitination
SH2B2	up-regulates	CBL	binding
CBL	down-regulates	PIK3R1	ubiquitination
CBL	down-regulates	PIK3R2	ubiquitination
EGFR	up-regulates	CBL	relocalization
GRB2	up-regulates	CBL	relocalization
SH3GLB1	up-regulates	CBL	binding
UBASH3B	down-regulates	CBL	binding
CBL	down-regulates	LRIG1	ubiquitination
LRIG1	up-regulates	CBL	binding
ERBB4	up-regulates	CBL	binding
ABI1	up-regulates	CBL	binding
CBL	“down-regulates quantity by destabilization”	ABL1	ubiquitination
CBL	“down-regulates quantity by destabilization”	MET	ubiquitination
CBL	“down-regulates quantity by destabilization”	CFLAR	ubiquitination
SH3KBP1	up-regulates	CBL	binding
PTPRJ	“down-regulates activity”	CBL
PRKCA	“down-regulates quantity”	CBL	phosphorylation
CBL	down-regulates	PI3K	ubiquitination
CBL	“down-regulates activity”	KIT	ubiquitination
Ub:E2	“up-regulates activity”	CBL	ubiquitination
CBL	“down-regulates quantity by destabilization”	PDGFRB	polyubiquitination
CBL	“down-regulates quantity by destabilization”	EPHA2	binding
CBL	“down-regulates quantity by destabilization”	LCK	polyubiquitination
CBL	“down-regulates activity”	SYK	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 123 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	58.4×	5e-11
Activation of BAD and translocation to mitochondria	7	57.9×	8e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	51.1×	2e-09
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	9	50.8×	1e-11
Regulation of signaling by CBL	9	48.6×	1e-11
Signaling by ERBB2 ECD mutants	6	43.8×	1e-07
Activation of BH3-only proteins	8	43.2×	6e-10
Downstream signal transduction	10	41.4×	7e-12

GO biological processes:

GO term	Partners	Fold	FDR
T cell differentiation	6	21.3×	6e-05
epidermal growth factor receptor signaling pathway	9	20.6×	2e-07
phosphatidylinositol 3-kinase/protein kinase B signal transduction	10	19.5×	5e-08
peptidyl-tyrosine phosphorylation	5	19.5×	5e-04
ephrin receptor signaling pathway	6	19.1×	9e-05
ERK1 and ERK2 cascade	6	17.7×	1e-04
protein targeting	5	17.0×	8e-04
insulin receptor signaling pathway	7	14.4×	9e-05

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 3 cancer types — ALL, AML, ESCA.

Clinical variants and AI predictions

ClinVar

2431 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	14
Uncertain significance	1419
Likely benign	717
Benign	96

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
13809	NM_005188.4(CBL):c.1168G>T (p.Asp390Tyr)	Pathogenic
1712083	NM_005188.4(CBL):c.1103_1108del (p.Tyr368_Glu369del)	Pathogenic
180815	NM_005188.4(CBL):c.1096-1G>T	Pathogenic
180826	NM_005188.2:c.1227+2_1227+3delTACinsAAG	Pathogenic
29824	NM_005188.4(CBL):c.1112A>G (p.Tyr371Cys)	Pathogenic
3772040	NM_005188.4(CBL):c.1221_1227+20del	Pathogenic
40401	NM_005188.4(CBL):c.306T>G (p.Tyr102Ter)	Pathogenic
40404	NM_005188.4(CBL):c.1076_1087del (p.Asp359_Lys362del)	Pathogenic
40405	NM_005188.4(CBL):c.1199T>G (p.Met400Arg)	Pathogenic
40407	NM_005188.4(CBL):c.1227+2_1227+4delinsAAG	Pathogenic
652390	NC_000011.9:g.(?118967698)(119170501_?)del	Pathogenic
689750	NM_005188.4(CBL):c.1096-2A>T	Pathogenic
1053208	NM_005188.4(CBL):c.1100A>G (p.Gln367Arg)	Likely pathogenic
1334208	NM_005188.4(CBL):c.1516C>T (p.Arg506Ter)	Likely pathogenic
1334287	NM_005188.4(CBL):c.1930G>T (p.Asp644Tyr)	Likely pathogenic
1386412	NM_005188.4(CBL):c.1259G>T (p.Arg420Leu)	Likely pathogenic
1427090	NM_005188.4(CBL):c.1112_1114del (p.Tyr371del)	Likely pathogenic
1700195	NM_005188.4(CBL):c.1007+2T>A	Likely pathogenic
1794421	NM_005188.4(CBL):c.1109_1111dup (p.Leu370_Tyr371insLeu)	Likely pathogenic
2575960	NM_005188.4(CBL):c.1178T>A (p.Ile393Asn)	Likely pathogenic
2662914	NM_005188.4(CBL):c.1142G>T (p.Cys381Phe)	Likely pathogenic
3033769	NM_005188.4(CBL):c.1096-6_1101delinsATTATGAATTTTTTTAAAT	Likely pathogenic
3252722	NM_005188.4(CBL):c.1228-2A>C	Likely pathogenic
4686183	NM_005188.4(CBL):c.1237G>T (p.Gly413Cys)	Likely pathogenic
4800612	NM_005188.4(CBL):c.1192C>A (p.His398Asn)	Likely pathogenic
949693	NM_005188.4(CBL):c.1112A>T (p.Tyr371Phe)	Likely pathogenic

SpliceAI

4821 predictions. Top by Δscore:

Variant	Effect	Δscore
11:119232555:A:G	donor_gain	1.0000
11:119232564:G:T	donor_gain	1.0000
11:119232583:GAAAA:G	donor_gain	1.0000
11:119232587:A:AG	donor_gain	1.0000
11:119271718:ATTCT:A	acceptor_gain	1.0000
11:119271732:TA:T	acceptor_loss	1.0000
11:119271734:GGC:G	acceptor_gain	1.0000
11:119271877:GAAAA:G	donor_gain	1.0000
11:119271878:AAAA:A	donor_gain	1.0000
11:119271878:AAAAG:A	donor_loss	1.0000
11:119271879:AAA:A	donor_gain	1.0000
11:119271879:AAAGT:A	donor_loss	1.0000
11:119271880:AA:A	donor_gain	1.0000
11:119271880:AAG:A	donor_loss	1.0000
11:119271881:AGTA:A	donor_loss	1.0000
11:119271882:G:GG	donor_gain	1.0000
11:119271882:GTA:G	donor_loss	1.0000
11:119271883:TAAGT:T	donor_loss	1.0000
11:119273866:A:AG	acceptor_gain	1.0000
11:119273867:G:GG	acceptor_gain	1.0000
11:119274020:TTCAG:T	donor_loss	1.0000
11:119274021:TCAGG:T	donor_loss	1.0000
11:119274023:AGGT:A	donor_loss	1.0000
11:119274024:GG:G	donor_loss	1.0000
11:119274026:T:A	donor_loss	1.0000
11:119274830:A:AG	acceptor_gain	1.0000
11:119274831:G:GG	acceptor_gain	1.0000
11:119274831:GCC:G	acceptor_gain	1.0000
11:119274831:GCCC:G	acceptor_gain	1.0000
11:119274831:GCCCT:G	acceptor_gain	1.0000

AlphaMissense

5938 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:119206595:T:A	W60R	1.000
11:119206595:T:C	W60R	1.000
11:119206602:T:C	L62P	1.000
11:119206605:T:A	M63K	1.000
11:119206605:T:G	M63R	1.000
11:119206607:G:C	D64H	1.000
11:119206608:A:T	D64V	1.000
11:119232455:G:C	R68P	1.000
11:119232460:T:C	C70R	1.000
11:119232461:G:A	C70Y	1.000
11:119232461:G:T	C70F	1.000
11:119232462:T:G	C70W	1.000
11:119232476:T:C	L75P	1.000
11:119232482:T:A	L77Q	1.000
11:119232482:T:C	L77P	1.000
11:119232482:T:G	L77R	1.000
11:119232484:A:G	K78E	1.000
11:119232486:G:C	K78N	1.000
11:119232486:G:T	K78N	1.000
11:119232489:T:A	N79K	1.000
11:119232489:T:G	N79K	1.000
11:119232490:A:C	S80R	1.000
11:119232492:C:A	S80R	1.000
11:119232492:C:G	S80R	1.000
11:119232493:C:A	P81T	1.000
11:119232493:C:T	P81S	1.000
11:119232494:C:A	P81Q	1.000
11:119232494:C:G	P81R	1.000
11:119232496:C:A	P82T	1.000
11:119232496:C:T	P82S	1.000

dbSNP variants (sampled 300 via entrez): RS1000011748 (11:119287098 A>G), RS1000015438 (11:119274059 T>C,G), RS1000024416 (11:119235700 A>G), RS1000033026 (11:119233346 G>A), RS1000052239 (11:119264776 C>A,G), RS1000092699 (11:119204786 T>C), RS1000142047 (11:119272196 A>G), RS1000151745 (11:119218476 C>T), RS1000163906 (11:119226969 T>C), RS1000207407 (11:119271408 G>A), RS1000220016 (11:119267627 A>G), RS1000228108 (11:119226375 CTG>C), RS1000259142 (11:119226684 C>G,T), RS1000279809 (11:119281528 T>C), RS1000292120 (11:119215487 T>G)

Disease associations

OMIM: gene MIM:165360 | disease phenotypes: MIM:613563, MIM:607785, MIM:163950, MIM:617290, MIM:608093, MIM:614750

GenCC curated gene-disease

Disease	Classification	Inheritance
CBL-related disorder	Definitive	Autosomal dominant
juvenile myelomonocytic leukemia	Strong	Autosomal dominant
Noonan syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
CBL-related disorder	Definitive	AD

Mondo (17): RASopathy (MONDO:0021060), CBL-related disorder (MONDO:0013308), juvenile myelomonocytic leukemia (MONDO:0011908), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), hereditary neoplastic syndrome (MONDO:0015356), Noonan syndrome (MONDO:0018997), rhabdomyosarcoma (MONDO:0005212), intellectual disability (MONDO:0001071), epilepsy, early-onset (MONDO:0957599), malignant germ cell tumor of ovary (MONDO:0018171), Noonan syndrome 1 (MONDO:0008104), neurodevelopmental disorder (MONDO:0700092), congenital heart disease (MONDO:0005453), B-lymphoblastic leukemia/lymphoma with hyperdiploidy (MONDO:0035943), DPAGT1-congenital disorder of glycosylation (MONDO:0011964)

Orphanet (13): RASopathy (Orphanet:536391), Noonan syndrome-like disorder with juvenile myelomonocytic leukemia (Orphanet:363972), Juvenile myelomonocytic leukemia (Orphanet:86834), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), Inherited cancer-predisposing syndrome (Orphanet:140162), Noonan syndrome (Orphanet:648), Rhabdomyosarcoma (Orphanet:780), Malignant germ cell tumor of ovary (Orphanet:35807), B-lymphoblastic leukemia/lymphoma with hyperdiploidy (Orphanet:585936), Congenital myasthenic syndrome with glycosylation defect (Orphanet:353327), Congenital myasthenic syndrome (Orphanet:590), DPAGT1-CDG (Orphanet:86309), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

143 total (30 of 143 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000078	Abnormality of the genital system
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000391	Thickened helices
HP:0000396	Overfolded helix
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000463	Anteverted nares
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000474	Thickened nuchal skin fold
HP:0000476	Cystic hygroma
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000520	Proptosis

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST001337_33	Platelet count	8.000000e-11
GCST004603_68	Platelet count	3.000000e-43
GCST004603_69	Platelet count	5.000000e-11
GCST004607_35	Plateletcrit	5.000000e-52
GCST004607_36	Plateletcrit	3.000000e-32
GCST004611_185	High light scatter reticulocyte count	2.000000e-11
GCST004612_119	High light scatter reticulocyte percentage of red cells	4.000000e-10
GCST004619_164	Reticulocyte fraction of red cells	4.000000e-15
GCST004622_115	Reticulocyte count	5.000000e-17
GCST005991_26	Platelet count	4.000000e-34
GCST011345_18	Triglyceride levels	2.000000e-09
GCST012032_10	Platelet count	2.000000e-17
GCST90002385_216	High light scatter reticulocyte count	9.000000e-19
GCST90002386_364	High light scatter reticulocyte percentage of red cells	4.000000e-17
GCST90002392_362	Mean corpuscular volume	1.000000e-12
GCST90002397_406	Mean spheric corpuscular volume	1.000000e-17
GCST90002400_478	Plateletcrit	7.000000e-76
GCST90002400_479	Plateletcrit	6.000000e-55
GCST90002402_394	Platelet count	4.000000e-173
GCST90002402_395	Platelet count	2.000000e-46
GCST90002405_296	Reticulocyte count	2.000000e-24
GCST90002406_330	Reticulocyte fraction of red cells	4.000000e-22

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0007986	reticulocyte count
EFO:0004530	triglyceride measurement

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D054429	Leukemia, Myelomonocytic, Juvenile	C04.557.337.539.525; C15.378.190.615.520; C15.378.508.539.525
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D065886	Neurodevelopmental Disorders	F03.625
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
D012208	Rhabdomyosarcoma	C04.557.450.590.550.660; C04.557.450.795.550.660
C535748	Congenital disorder of glycosylation type 1J (supp.)
C537846	Noonan like syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066351 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

48 potent at pChembl≥5 of 50 total, top 48 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	Ki	0.2	nM	CHEMBL6134621
9.15	Ki	0.7	nM	CHEMBL6120549
9.05	Ki	0.9	nM	CHEMBL6102700
8.89	Ki	1.3	nM	CHEMBL6103468
8.64	EC50	2.3	nM	CHEMBL6134621
8.51	Ki	3.1	nM	CHEMBL6147468
8.46	Ki	3.5	nM	CHEMBL6133335
8.40	EC50	4	nM	CHEMBL6102700
8.30	Ki	5	nM	CHEMBL6133395
8.30	Ki	5	nM	CHEMBL6134158
8.24	EC50	5.7	nM	CHEMBL6120549
8.18	Ki	6.6	nM	CHEMBL6141556
7.94	Ki	11.4	nM	CHEMBL6083093
7.85	EC50	14.2	nM	CHEMBL6103468
7.82	Ki	15	nM	CHEMBL6147378
7.73	Ki	18.5	nM	CHEMBL6103305
7.65	EC50	22.4	nM	CHEMBL6143001
7.59	Ki	25.7	nM	CHEMBL6078127
7.51	EC50	30.9	nM	CHEMBL6133395
7.50	EC50	31.9	nM	CHEMBL6147468
7.47	EC50	33.8	nM	CHEMBL6134158
7.43	EC50	37.2	nM	CHEMBL6133335
7.40	IC50	40	nM	CHEMBL5568675
7.40	IC50	40	nM	CHEMBL5591412
7.30	IC50	50	nM	CHEMBL5570218
7.30	IC50	50	nM	CHEMBL5565433
7.16	EC50	68.5	nM	CHEMBL6141556
7.10	IC50	80	nM	CHEMBL5593951
6.96	EC50	110.5	nM	CHEMBL6103305
6.80	IC50	160	nM	CHEMBL5549968
6.80	EC50	159.7	nM	CHEMBL6147378
6.75	EC50	177	nM	CHEMBL6083093
6.72	IC50	190	nM	CHEMBL5575731
6.70	IC50	200	nM	CHEMBL5571356
6.48	IC50	330	nM	CHEMBL5595595
6.48	IC50	330	nM	CHEMBL5571987
6.39	IC50	410	nM	CHEMBL5542469
6.34	IC50	460	nM	CHEMBL5573269
6.33	EC50	468.8	nM	CHEMBL6078127
6.24	IC50	580	nM	CHEMBL5574553
6.07	IC50	860	nM	CHEMBL5563999
6.06	IC50	880	nM	CHEMBL5592825
6.02	IC50	960	nM	CHEMBL5575462
5.87	IC50	1340	nM	CHEMBL5569665
5.77	IC50	1700	nM	CHEMBL5567426
5.66	IC50	2200	nM	CHEMBL5570276
5.20	IC50	6300	nM	CHEMBL5571500
5.18	IC50	6550	nM	CHEMBL5571480

PubChem BioAssay actives

21 with measured affinity, of 24 total; 21 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(2S)-pent-3-yn-2-yl]-5-(trifluoromethyl)pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.0400	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(1-methyltriazol-4-yl)methyl]-5-(trifluoromethyl)pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.0400	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(1S)-1-(1-methylpyrazol-4-yl)ethyl]-5-(trifluoromethyl)pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.0500	uM
(2S)-2-[3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-2-oxo-5-(trifluoromethyl)-1-pyridinyl]propanenitrile	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.0500	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(1R)-1-(1-methylpyrazol-4-yl)ethyl]-5-(trifluoromethyl)pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.0800	uM
1-but-2-ynyl-3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-5-(trifluoromethyl)pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.1600	uM
1-[(1-methylimidazol-4-yl)methyl]-3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-5-(trifluoromethyl)pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.1900	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(1-methylpyrazol-4-yl)methyl]-5-(trifluoromethyl)pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.2000	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[[(3S)-1-methylpyrrolidin-3-yl]methyl]-5-(trifluoromethyl)pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.3300	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-5-(trifluoromethyl)pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.3300	uM
3-[3-[(R)-cyclobutyl-(4-methyl-1,2,4-triazol-3-yl)methyl]phenyl]-5-(trifluoromethyl)-1H-pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.4100	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(1-methylpiperidin-4-yl)methyl]-5-(trifluoromethyl)pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.4600	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-5-(trifluoromethyl)-1H-pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.5800	uM
1-methyl-5-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-(trifluoromethyl)-7H-pyrrolo[2,3-b]pyridin-6-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.8600	uM
1-methyl-3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-5-(trifluoromethyl)pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.8800	uM
3-[(4-methyl-1,2,4-triazol-3-yl)methyl]-3-[3-[2-oxo-5-(trifluoromethyl)-1H-pyridin-3-yl]phenyl]cyclobutane-1-carbonitrile	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	0.9600	uM
5-cyclopropyl-3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1H-pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	1.3400	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-5-(trifluoromethoxy)-1H-pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	1.7000	uM
3-[3-[1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-5-(trifluoromethyl)-1H-pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	2.2000	uM
5-methyl-3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1H-pyridin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	6.3000	uM
3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-5-(trifluoromethyl)-1H-pyrazin-2-one	2098912: Inhibition of cCbl (unknown origin) by TR-FRET assay	ic50	6.5500	uM

CTD chemical–gene interactions

57 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression, affects cotreatment	3
Benzo(a)pyrene	increases expression	3
Acetaminophen	increases expression	2
Dronabinol	decreases expression, increases expression, affects reaction	2
FR900359	decreases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
geldanamycin	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
bisphenol A	increases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
saikosaponin D	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline	decreases reaction, increases phosphorylation	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
torcetrapib	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
tetraarsenic tetrasulfide	affects cotreatment, increases expression	1
Imatinib Mesylate	affects cotreatment, increases expression	1
Bortezomib	decreases activity, increases activity, increases reaction	1
Resveratrol	decreases expression	1
Arsenic Trioxide	increases reaction, increases expression, decreases activity, increases activity	1
Vorinostat	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Vehicle Emissions	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 2 binding, 2 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5540670	Binding	Inhibition of cCbl (unknown origin) by TR-FRET assay	Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors. — J Med Chem
CHEMBL6077616	Toxicity	Displacement of fluorescent tracer from C-CBL (46 to 435 residues) (unknown origin) preincubated for 15 mins followed by fluorescent tracer addition and measured after 1 hr by HTRF method	Potential Therapeutic Benefit of the Selective Inhibitors of Casitas B Cell Lymphoma-b (CBL-B) in Cancer Immunotherapy. — ACS Med Chem Lett

Cellosaurus cell lines

9 cell lines: 7 cancer cell line, 1 transformed cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2TJ	Abcam HEK293T CBL KO	Transformed cell line	Female
CVCL_B8CH	Abcam HCT 116 CBL KO	Cancer cell line	Male
CVCL_B8TC	Abcam MCF-7 CBL KO	Cancer cell line	Female
CVCL_B9EN	Abcam A-549 CBL KO	Cancer cell line	Male
CVCL_D5KT	NPC268	Cancer cell line	Female
CVCL_D7LU	Ubigene A-549 CBL KO	Cancer cell line	Male
CVCL_SH05	HAP1 CBL (-) 1	Cancer cell line	Male
CVCL_VN17	CHOPi001-A	Induced pluripotent stem cell	Female
CVCL_XM45	HAP1 CBL (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

307 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01339988	PHASE4	UNKNOWN	Busulfan and Cyclophosphamide Instead of Total Boby Irradiation (TBI) and Cyclophosphamide for Hematological Malignancies Hematocrit (HCT)
NCT00002798	PHASE3	COMPLETED	Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Children With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
NCT00152139	PHASE3	COMPLETED	Stem Cell Transplantation for Patients With Hematologic Malignancies
NCT00186823	PHASE3	COMPLETED	Haploidentical Stem Cell Transplantation for Patients With Hematologic Malignancies
NCT00450450	PHASE3	COMPLETED	Donor Bone Marrow Transplant With or Without G-CSF in Treating Young Patients With Hematologic Cancer or Other Diseases
NCT00799461	PHASE3	COMPLETED	Internet-Based Program With or Without Telephone-Based Problem-Solving Training in Helping Long-Term Survivors of Hematopoietic Stem Cell Transplant Cope With Late Complications
NCT00843882	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia
NCT01241500	PHASE3	COMPLETED	Randomized Study of ON 01910.Na in Refractory Myelodysplastic Syndrome Patients With Excess Blasts
NCT01305200	PHASE3	COMPLETED	Supersaturated Calcium Phosphate Rinse in Preventing Oral Mucositis in Young Patients Undergoing Autologous or Donor Stem Cell Transplant
NCT01749111	PHASE3	TERMINATED	Comparison Between Cyclophosphamide and Combination of Methotrexate + Calcineurin Inhibitor for GVHD Prophylaxis
NCT01928537	PHASE3	COMPLETED	Efficacy and Safety of IV Rigosertib in MDS Patients With Excess Blasts Progressing After Azacitidine or Decitabine
NCT03306264	PHASE3	COMPLETED	Study of ASTX727 vs IV Decitabine in Participants With MDS, CMML, and AML
NCT04842604	PHASE3	COMPLETED	Continuation Study of B1371019(NCT03416179) and B1371012(NCT02367456) Evaluating Azacitidine With Or Without Glasdegib In Patients With Previously Untreated AML, MDS or CMML
NCT05515029	PHASE3	ACTIVE_NOT_RECRUITING	Preventing of GVHD With Post-transplantation Cyclophosphamide, Abatacept, Vedolizumab and Calcineurin Inhibitor at Patients With Hemoblastosis
NCT06647862	PHASE3	RECRUITING	IMM01+Azacitidine VS Placebo +Azacitidine in Patients With Newly Diagnosed Chronic Myelomonocytic Leukemia (CMML1-2)
NCT00452725	PHASE3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	PHASE3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	PHASE3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	PHASE3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	PHASE3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT00015990	PHASE2	COMPLETED	Thalidomide in Treating Patients With Myelodysplastic Syndrome
NCT00025038	PHASE2	COMPLETED	Combination Chemotherapy Followed By Donor Bone Marrow or Umbilical Cord Blood Transplant in Treating Children With Newly Diagnosed Juvenile Myelomonocytic Leukemia
NCT00039416	PHASE2	COMPLETED	Imatinib Mesylate in Treating Patients With Myelofibrosis
NCT00067808	PHASE2	COMPLETED	Study of Three Different Schedules of Low-Dose Decitabine in Myelodysplastic Syndrome (MDS)
NCT00079313	PHASE2	COMPLETED	Imatinib (Gleevec(Registered Trademark)) to Treat Chronic Myelomonocytic Leukemia and Atypical Chronic Myelogenous Leukemia
NCT00084916	PHASE2	COMPLETED	CCI-779 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndromes, or Chronic Myelogenous Leukemia in Blastic Phase
NCT00113321	PHASE2	TERMINATED	Low-Dose Decitabine in Myelodysplastic Syndrome Post Azacytidine Failure
NCT00118352	PHASE2	COMPLETED	Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer
NCT00119366	PHASE2	TERMINATED	Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Total Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome
NCT00136409	PHASE2	COMPLETED	A Study of Gleevec in Patients With Idiopathic Myelofibrosis or Chronic Myelomonocytic Leukemia (CMML)
NCT00143559	PHASE2	COMPLETED	Stem Cell Transplantation as Immunotherapy for Hematologic Malignancies
NCT00145613	PHASE2	COMPLETED	Haploidentical Stem Cell Transplant for Treatment Refractory Hematological Malignancies
NCT00171912	PHASE2	COMPLETED	Imatinib Mesylate in Patients With Various Types of Malignancies Involving Activated Tyrosine Kinase Enzymes
NCT00299156	PHASE2	COMPLETED	Oral Clofarabine Study in Patients With Myelodysplastic Syndrome
NCT00309907	PHASE2	COMPLETED	Etanercept in Treating Young Patients With Idiopathic Pneumonia Syndrome After Undergoing a Donor Stem Cell Transplant
NCT00313586	PHASE2	COMPLETED	Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia
NCT00381550	PHASE2	COMPLETED	3-AP and Fludarabine in Treating Patients With Myeloproliferative Disorders, Chronic Myelomonocytic Leukemia, or Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia
NCT00387426	PHASE2	TERMINATED	Sunitinib in Treating Patients With Idiopathic Myelofibrosis
NCT00397813	PHASE2	COMPLETED	Fludarabine Phosphate and Total Body Irradiation Followed by a Donor Peripheral Stem Cell Transplant in Treating Patients With Myelodysplastic Syndromes or Myeloproliferative Disorders