MPL

Summary

MPL (MPL proto-oncogene, thrombopoietin receptor, HGNC:7217) is a protein-coding gene on chromosome 1p34.2, encoding Thrombopoietin receptor (P40238). Receptor for thrombopoietin that regulates hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation.

In 1990 an oncogene, v-mpl, was identified from the murine myeloproliferative leukemia virus that was capable of immortalizing bone marrow hematopoietic cells from different lineages. In 1992 the human homologue, named, c-mpl, was cloned. Sequence data revealed that c-mpl encoded a protein that was homologous with members of the hematopoietic receptor superfamily. Presence of anti-sense oligodeoxynucleotides of c-mpl inhibited megakaryocyte colony formation. The ligand for c-mpl, thrombopoietin, was cloned in 1994. Thrombopoietin was shown to be the major regulator of megakaryocytopoiesis and platelet formation. The protein encoded by the c-mpl gene, CD110, is a 635 amino acid transmembrane domain, with two extracellular cytokine receptor domains and two intracellular cytokine receptor box motifs . TPO-R deficient mice were severely thrombocytopenic, emphasizing the important role of CD110 and thrombopoietin in megakaryocyte and platelet formation. Upon binding of thrombopoietin CD110 is dimerized and the JAK family of non-receptor tyrosine kinases, as well as the STAT family, the MAPK family, the adaptor protein Shc and the receptors themselves become tyrosine phosphorylated.

Source: NCBI Gene 4352 — RefSeq curated summary.

At a glance

• Gene–disease (curated): thrombocythemia 2 (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 947 total — 77 pathogenic, 94 likely-pathogenic
• Phenotypes (HPO): 89
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): ambiguous (mixed evidence) across 1 cancer types
• MANE Select transcript: NM_005373

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7217
Approved symbol	MPL
Name	MPL proto-oncogene, thrombopoietin receptor
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	CD110, TPOR, THPOR
Ensembl gene	ENSG00000117400
Ensembl biotype	protein_coding
OMIM	159530
Entrez	4352

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000372470, ENST00000413998, ENST00000638732, ENST00000643351, ENST00000967221

RefSeq mRNA: 1 — MANE Select: NM_005373 NM_005373

CCDS: CCDS483

Canonical transcript exons

ENST00000372470 — 12 exons

Exon	Start	End
ENSE00000769664	43352216	43352303
ENSE00000769665	43349263	43349359
ENSE00000769667	43348843	43349002
ENSE00000769669	43346792	43346934
ENSE00000769670	43346445	43346629
ENSE00000769671	43340387	43340513
ENSE00000769672	43339964	43340126
ENSE00000769673	43339271	43339569
ENSE00000769674	43338542	43338720
ENSE00000769675	43338099	43338231
ENSE00003897233	43352518	43354466
ENSE00003897867	43337818	43337927

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 78.45.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4222 / max 128.3385, expressed in 42 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2508	0.4222	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.45	gold quality
mononuclear cell	CL:0000842	74.20	gold quality
monocyte	CL:0000576	74.15	gold quality
leukocyte	CL:0000738	73.33	gold quality
parotid gland	UBERON:0001831	66.20	gold quality
right frontal lobe	UBERON:0002810	64.57	gold quality
bone marrow cell	CL:0002092	63.58	silver quality
endothelial cell	CL:0000115	63.36	gold quality
bronchial epithelial cell	CL:0002328	63.27	silver quality
sural nerve	UBERON:0015488	62.90	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	62.75	gold quality
epithelium of bronchus	UBERON:0002031	62.12	silver quality
left ovary	UBERON:0002119	62.01	gold quality
Brodmann (1909) area 9	UBERON:0013540	61.66	gold quality
prefrontal cortex	UBERON:0000451	61.57	gold quality
bronchus	UBERON:0002185	61.51	silver quality
ovary	UBERON:0000992	61.36	gold quality
heart left ventricle	UBERON:0002084	61.04	gold quality
cardiac ventricle	UBERON:0002082	60.74	gold quality
apex of heart	UBERON:0002098	60.71	gold quality
vena cava	UBERON:0004087	60.59	gold quality
blood	UBERON:0000178	60.33	gold quality
cingulate cortex	UBERON:0003027	60.25	gold quality
right coronary artery	UBERON:0001625	60.18	gold quality
islet of Langerhans	UBERON:0000006	60.06	gold quality
anterior cingulate cortex	UBERON:0009835	60.01	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	59.90	gold quality
bone marrow	UBERON:0002371	59.80	gold quality
blood vessel layer	UBERON:0004797	59.52	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	59.46	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-6	yes	5635.34
E-GEOD-76312	yes	3624.53
E-MTAB-9067	yes	632.83
E-GEOD-130473	yes	442.59
E-ANND-3	yes	5.93
E-MTAB-9801	yes	5.88

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, FLI1, GATA1, MBD2, PLAGL2, RUNX1, SP1, ZBTB16

miRNA regulators (miRDB)

94 targeting MPL, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-636	99.80	69.58	1500

Literature-anchored findings (GeneRIF, showing 40)

• binding to platelet thrombopoietin receptor is directly involved in human thrombopoietin plasma level regulation (PMID:11961237)
• expressed in megakaryocytes in essential thrombocythemia (PMID:12010817)
• The expression pattern of c-mpl in megakaryocytes correlates with thrombotic risk in essential thrombocythemia. (PMID:12091373)
• A new mutation of MPL, Trp(508) to Ser(508) in the intracellular domain of MPL, induces factor-independent growth in Ba/F3 cells & constitutively activates 3 distinct signaling pathways, SHC-Ras-Raf-MAPK/JNK, JAK-STAT, and PI3K-Akt-Bad. (PMID:12145691)
• The cytoplasmic domain of Mpl receptor transduces exclusive signals in embryonic and fetal hematopoietic cells. (PMID:12200367)
• Asn505 is an activating mutation with respect to the intracellular signaling and survival of cells in familial essential thrombocythemia deriving from a dominant-positive activating mutation of the c-MPL gene. (PMID:14764528)
• the promoter activity of myeloproliferative leukemia virus oncogene is modulated by transcription through a PKC-dependent pathway (PMID:14995067)
• c-Mpl truncated isoform with an essential C-terminal peptide is required for a proteolytic process (PMID:15210714)
• K39N represents an identified functional Mpl polymorphism and is associated with altered protein expression of Mpl and a clinical phenotype of thrombocytosis. (PMID:15269348)
• may play a role in hematopoietic inhibition during HIV-1 infection, and control of its expression levels may aid in hematopoietic recovery and thereby reduce the incidence of cytopenias occurring in infected individuals (PMID:15452260)
• expression of TPO receptor on platelets until 1 month after birth cause a decreased TPO clearance and keep a high level of free TPO in blood, resulting in the subsequent thrombocytosis in preterm infants. (PMID:15647951)
• a C-terminal AML1 mutation leads to a decrease in Mpl receptor expression in familial thrombocytopenia (PMID:15741216)
• Interaction with JAK2 or Tyk2 appears to protect the receptor from proteasome degradation. Sequences encompassing Box1 and Box2 regions of the receptor cytosolic domain and an intact JAK2 or Tyk2 FERM domain are required for these effects. (PMID:15899890)
• PRV-1 overexpression is associated with a significantly increased risk of thrombosis, whereas decreased c-Mpl expression is not (PMID:15951300)
• In this study, we report the binding of hNUDC to the extracellular domain of the thrombopoietin receptor (Mpl) as detected by the yeast two-hybrid system, GST pull-down, and co-immunoprecipitation. (PMID:16088917)
• in HIV infected patients, both the serum thrombopoietin (TPO) levels and the TPO-c-Mpl complexes on the platelet surface were significantly elevated (PMID:16454716)
• analysis of MPL mutations in patients suffering from congenital amegakaryocytic thrombocytopenia (PMID:16470591)
• Activation of JAK-STAT signaling via a somatic activating mutation in the transmembrane domain of MPL (MPLW515L) is an important pathogenetic event in patients with JAK2V617F-negative MF. (PMID:16834459)
• MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders (PMID:16868251)
• expression of JAK2 stabilizes mature TpoR and thus further increases its surface expression. This JAK2 effect depends on the Box 1 region, the only JAK2 interacting site in the TpoR (PMID:17052978)
• The expression of mRNA of C-MPL in platelets is a clear band by RT-PCR methods. (PMID:17157161)
• THPO upregulates c-mpl expression during formation of CD34+ cells. (PMID:17379761)
• it was concluded that the oncogenic event in idiopathic myelofibrosis associated with the MPLW515L/K mutations probably occurs in a progenitor cell common to both myeloid and lymphoid cells, such as the pluripotent haematopoietic stem cell (PMID:17408398)
• MPL mutation in myelofibrosis characterises patients with more severe anaemic phenotype (PMID:17408465)
• MPLW515K, but not JAK2V617F, is expressed in in vitro expanded CD4+ T lymphocytes from primary myelofibrosis patients (PMID:17507998)
• Clonal myelopoiesis antedates acquisition of JAK2V617F or MPLW515L/K mutations. (PMID:17540852)
• hNUDC binds to cell surface-captured Mpl.Co-expression of Mpl-EGFP and hNUDC-DsRed led to the release of hNUDC-DsRed into the culture medium (PMID:17658515)
• Mutations in MPL is associated with congenital amegakaryocytic thrombocytopenia (PMID:17666371)
• The MPL W515L or K mutation induces a spontaneous megakaryocyte (MK) differentiation. (PMID:17709604)
• MPL gene mutations were not associated with erythrocytosis, but segregated primarily with the phenotypes of thrombocytosis, extramedullary disease, myelofibrosis, and osteosclerosis. (PMID:17920755)
• Expression of c-mpl in CD34+ BMHCs and platelets of polycythemia vera patients was not obviously abnormal. (PMID:17956691)
• no MPL (myeloproliferative leukemia virus oncogene thrombopoietin recept) W515L/K mutations were found in any patients with refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T) (PMID:18040685)
• These data demonstrate that dimerization of a single cytokine receptor can deliver a profound expansion signal in both uncommitted and lymphoid-committed human hematopoietic progenitors. (PMID:18174381)
• diagnostic and prognostic value of JAK2 and MPL515 mutations in 241 SVT patients (PMID:18250227)
• Sp1 sites in the c-mpl promoter enhancer region and Ets elements in front of the transcription start site are critical for c-mpl gene expression. (PMID:18295514)
• review of roles of Jak2, Jak3, and MPL mutations in signal transduction and etiology of myeloid malignancies (PMID:18297515)
• a severe clinical course of congenital amegakaryocytic thrombocytopenia may be expected when mutations lead to absent Mpl expression or signalling in patients with missense mutations (PMID:18422784)
• MPL mutations lacked prognostic significance with respect to thrombosis, major hemorrhage, myelofibrotic transformation or survival. (PMID:18451306)
• MPL W515L mutations may contribute to the primary molecular pathogenesis of Chinese patients with ET (PMID:18464114)
• c-Mpl cytoplasmic YRRL motifs are responsible for both Tpo-mediated internalization via interactions with AP2 and lysosomal targeting after endocytosis. (PMID:18487512)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mpl	ENSDARG00000039222
mus_musculus	Mpl	ENSMUSG00000006389
rattus_norvegicus	Mpl	ENSRNOG00000028377

Paralogs (7): IL4R (ENSG00000077238), CSF2RB (ENSG00000100368), IL2RB (ENSG00000100385), IL21R (ENSG00000103522), IL9R (ENSG00000124334), IL7R (ENSG00000168685), EPOR (ENSG00000187266)

Protein

Protein identifiers

Thrombopoietin receptor — P40238 (reviewed: P40238)

Alternative names: Myeloproliferative leukemia protein, Proto-oncogene c-Mpl

All UniProt accessions (3): A0A2R8YE13, P40238, Q5JUY5

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for thrombopoietin that regulates hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation. Upon activation by THPO, induces rapid tyrosine phosphorylation and activation of JAK2, providing docking sites for many signaling proteins such as STAT5, SHIP/INPP5D, GRB2, SOS1 and PI3K. In turn, These signaling cascades lead to the proliferation, survival, and differentiation of megakaryocytes, ultimately leading to increased platelet production.

Subunit / interactions. Homodimer. Interacts with ATXN2L. Interacts with JAK2 and TYK2; these interactions increase MPL localization to the cell membrane. Interacts with THPO. Interacts with SHIP/INPP5D. Interacts with BTK. Interacts with SYK; this interaction negatively regulates THPO-mediated ERK1/2 signaling.

Subcellular location. Cell membrane. Golgi apparatus. Cell surface.

Tissue specificity. Expressed at a low level in a large number of cells of hematopoietic origin. Isoform 1 and isoform 2 are always found to be coexpressed.

Post-translational modifications. Phosphorylated at Tyr-591 in response to THPO stimulation. Ubiquitination at Lys-553 and Lys-573 targets MPL for degradation by both the lysosomal and proteasomal pathways. The E3 ubiquitin-protein ligase CBL significantly contributes to this ubiquitination.

Disease relevance. Amegakaryocytic thrombocytopenia, congenital, 1 (CAMT1) [MIM:604498] An autosomal recessive form of congenital amegakaryocytic thrombocytopenia, a hematologic disorder characterized by severe reduction of megakaryocytes and platelets at birth, and evolving into generalized bone marrow aplasia during childhood. The disease is caused by variants affecting the gene represented in this entry. Thrombocythemia 2 (THCYT2) [MIM:601977] A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes. The disease is caused by variants affecting the gene represented in this entry. Myelofibrosis with myeloid metaplasia (MMM) [MIM:254450] A chronic myeloproliferative disorder characterized by replacement of the bone marrow by fibrous tissue, extramedullary hematopoiesis, anemia, leukoerythroblastosis and hepatosplenomegaly. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding. The box 1 motif is required for JAK interaction and/or activation.

Similarity. Belongs to the type I cytokine receptor family. Type 1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P40238-1	1, C-mpl-P	yes
P40238-2	2, C-mpl-K

RefSeq proteins (1): NP_005364* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003528	Long_hematopoietin_rcpt_CS	Conserved_site
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015152	Growth/epo_recpt_lig-bind	Domain
IPR036116	FN3_sf	Homologous_superfamily

Pfam: PF09067

UniProt features (87 total): strand 31, sequence variant 17, disulfide bond 6, helix 6, glycosylation site 4, modified residue 3, mutagenesis site 3, turn 3, topological domain 2, cross-link 2, splice variant 2, domain 2, short sequence motif 2, signal peptide 1, chain 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8G04	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P40238-F1	73.44	0.33

Functional residue map

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

Post-translational modifications (5): 591, 626, 631, 553, 573

Disulfide bonds (6): 40–50, 77–93, 193–323, 194–241, 291–301, 334–352

Glycosylation sites (4): 117, 178, 298, 358

Mutagenesis-validated functional residues (3):

Position	Phenotype
528	about 75% loss of cell surface expression; when associated with a-529.
529	about 75% loss of cell surface expression; when associated with a-528.
591	exhibits enhanced and prolonged erk1/2 activation upon thpo stimulation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-76009	Platelet Aggregation (Plug Formation)

MSigDB gene sets: 305 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_PLATELET_AGGREGATION_PLUG_FORMATION, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, SP3_Q3, GOCC_CELL_SURFACE, BIOCARTA_TPO_PATHWAY, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, IRF7_01, GOBP_REGULATION_OF_HEMOPOIESIS

GO Biological Process (9): neutrophil homeostasis (GO:0001780), platelet formation (GO:0030220), monocyte homeostasis (GO:0035702), thrombopoietin-mediated signaling pathway (GO:0038163), positive regulation of lymphocyte proliferation (GO:0050671), cellular response to hypoxia (GO:0071456), positive regulation of platelet formation (GO:1905221), eosinophil homeostasis (GO:1990959), basophil homeostasis (GO:1990960)

GO Molecular Function (3): thrombopoietin receptor activity (GO:0038164), cytokine receptor activity (GO:0004896), protein binding (GO:0005515)

GO Cellular Component (7): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), nuclear membrane (GO:0031965), neuronal cell body (GO:0043025), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Platelet activation, signaling and aggregation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
leukocyte homeostasis	4
myeloid cell homeostasis	4
cellular anatomical structure	2
myeloid cell differentiation	1
platelet morphogenesis	1
anatomical structure formation involved in morphogenesis	1
chemokine-mediated signaling pathway	1
positive regulation of mononuclear cell proliferation	1
lymphocyte proliferation	1
regulation of lymphocyte proliferation	1
positive regulation of lymphocyte activation	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
positive regulation of cell morphogenesis	1
platelet formation	1
positive regulation of myeloid cell differentiation	1
regulation of platelet formation	1
cytokine receptor activity	1
thrombopoietin-mediated signaling pathway	1
transmembrane signaling receptor activity	1
cytokine-mediated signaling pathway	1
cytokine binding	1
immune receptor activity	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
nucleus	1
nuclear envelope	1
organelle membrane	1
somatodendritic compartment	1
cell body	1

Protein interactions and networks

STRING

985 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MPL	THPO	P40225	999
MPL	JAK2	O60674	904
MPL	CALR	P27797	889
MPL	KITLG	P21583	857
MPL	EPO	P01588	839
MPL	CD34	P28906	788
MPL	SH2B3	Q9UQQ2	757
MPL	IL3	P08700	755
MPL	ITGA2B	P08514	704
MPL	KIT	P10721	693
MPL	NUDC	Q9Y266	693
MPL	CSF3	P09919	669
MPL	TET2	Q6N021	644
MPL	CD38	P28907	615
MPL	GATA1	P15976	609

IntAct

17 interactions, top by confidence:

A	B	Type	Score
MPL	THPO	psi-mi:“MI:0407”(direct interaction)	0.600
THPO	MPL	psi-mi:“MI:0407”(direct interaction)	0.600
MPL	JAK2	psi-mi:“MI:0915”(physical association)	0.520
MPL	JAK2	psi-mi:“MI:0403”(colocalization)	0.520
MPL	JAK2	psi-mi:“MI:2364”(proximity)	0.520
JAK2	MPL	psi-mi:“MI:2364”(proximity)	0.520
MPL	EGFR	psi-mi:“MI:2364”(proximity)	0.480
MPL	ATXN2L	psi-mi:“MI:0915”(physical association)	0.370
ATXN2L	MPL	psi-mi:“MI:0915”(physical association)	0.370
MPL	FAM171A2	psi-mi:“MI:0914”(association)	0.350
MPL	MPL	psi-mi:“MI:0403”(colocalization)	0.350
MPL	PTEN	psi-mi:“MI:2364”(proximity)	0.270
MPL	TP53	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (37): MPL (Affinity Capture-MS), JAK2 (Affinity Capture-Western), ATXN2L (Two-hybrid), ATXN2L (Affinity Capture-Western), SOCS1 (Affinity Capture-Western), PDXP (Affinity Capture-MS), LRP12 (Affinity Capture-MS), ERCC6 (Affinity Capture-MS), EGFR (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), TSC2 (Affinity Capture-MS), ALX1 (Affinity Capture-MS), TYK2 (Affinity Capture-MS), GOLGA7 (Affinity Capture-MS), CTDNEP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LHF2, A0EQL2, D3YZF7, D7PDD4, O15533, O55237, O70394, O70540, O95866, P04278, P05111, P07994, P08689, P0C6B3, P0DP72, P15196, P17490, P18627, P40238, P55101, P60882, P97497, Q00657, Q08351, Q14393, Q14773, Q16671, Q3SWY4, Q5BK54, Q5NKT8, Q5TJE4, Q61790, Q61826, Q62588, Q6PZD2, Q6UVK1, Q6UWB1, Q7Z7M0, Q7Z7M1, Q86VR7

Diamond homologs: P40238, P40931, Q08351, P14753, P19235, Q07303, Q2KL21, Q9MYZ9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ATXN2L	down-regulates	MPL	binding
THPO	up-regulates	MPL	binding
GATA1	“up-regulates quantity by expression”	MPL	“transcriptional regulation”
FLI1	“up-regulates quantity by expression”	MPL	“transcriptional regulation”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: ambiguous (mixed evidence) across 1 cancer types — HNSC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	77
Likely pathogenic	94
Uncertain significance	301
Likely benign	374
Benign	14

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072631	NM_005373.3(MPL):c.1563C>A (p.Tyr521Ter)	Pathogenic
1073761	NM_005373.3(MPL):c.252del (p.Met84fs)	Pathogenic
1074655	NM_005373.3(MPL):c.1025del (p.Pro342fs)	Pathogenic
1236205	NM_005373.3(MPL):c.1670C>A (p.Ser557Ter)	Pathogenic
1301356	NM_005373.3(MPL):c.367C>T (p.Arg123Ter)	Pathogenic
1320277	NM_005373.3(MPL):c.1468+1G>C	Pathogenic
134822	NM_005373.3(MPL):c.235_236del (p.Leu79fs)	Pathogenic
1368759	NM_005373.3(MPL):c.842del (p.Pro281fs)	Pathogenic
1381492	NM_005373.3(MPL):c.605dup (p.Ala203fs)	Pathogenic
1382942	NM_005373.3(MPL):c.1346dup (p.Glu450fs)	Pathogenic
1395269	NM_005373.3(MPL):c.972_973del (p.Asp326fs)	Pathogenic
14154	NM_005373.3(MPL):c.556C>T (p.Gln186Ter)	Pathogenic
14155	NM_005373.3(MPL):c.1499del (p.Leu500fs)	Pathogenic
14158	NM_005373.3(MPL):c.305G>C (p.Arg102Pro)	Pathogenic
14159	NM_005373.3(MPL):c.1473G>A (p.Trp491Ter)	Pathogenic
14160	NM_005373.3(MPL):c.1566-1G>T	Pathogenic
14163	NM_005373.3(MPL):c.1514G>A (p.Ser505Asn)	Pathogenic
14165	NM_005373.3(MPL):c.1543_1544delinsAA (p.Trp515Lys)	Pathogenic
1436487	NM_005373.3(MPL):c.1248G>A (p.Trp416Ter)	Pathogenic
1442900	NM_005373.3(MPL):c.1378C>T (p.Gln460Ter)	Pathogenic
1448576	NM_005373.3(MPL):c.190C>T (p.Gln64Ter)	Pathogenic
1454277	NM_005373.3(MPL):c.1463_1466dup (p.Ala490fs)	Pathogenic
1455725	NM_005373.3(MPL):c.1219G>T (p.Glu407Ter)	Pathogenic
1455997	NM_005373.3(MPL):c.1489_1490del (p.Ala497fs)	Pathogenic
1456793	NM_005373.3(MPL):c.94del (p.Ala32fs)	Pathogenic
1456841	NM_005373.3(MPL):c.1305del (p.Asp434_Trp435insTer)	Pathogenic
1456884	NM_005373.3(MPL):c.1532_1535del (p.Leu511fs)	Pathogenic
1457364	NM_005373.3(MPL):c.1546C>T (p.Gln516Ter)	Pathogenic
1457605	NM_005373.3(MPL):c.189C>G (p.Tyr63Ter)	Pathogenic
1458516	NC_000001.10:g.(?43800988)(43803797_?)del	Pathogenic

SpliceAI

1994 predictions. Top by Δscore:

Variant	Effect	Δscore
1:43340385:A:AG	acceptor_gain	1.0000
1:43340386:G:GG	acceptor_gain	1.0000
1:43338715:GT:G	donor_gain	0.9900
1:43339961:AAG:A	acceptor_gain	0.9900
1:43339962:A:G	acceptor_gain	0.9900
1:43340385:AGT:A	acceptor_gain	0.9900
1:43340386:GT:G	acceptor_gain	0.9900
1:43340386:GTG:G	acceptor_gain	0.9900
1:43349051:G:T	donor_gain	0.9900
1:43349261:A:AG	acceptor_gain	0.9900
1:43349262:G:GG	acceptor_gain	0.9900
1:43349338:GGC:G	donor_gain	0.9900
1:43352215:G:GC	acceptor_loss	0.9900
1:43352215:GGA:G	acceptor_gain	0.9900
1:43352299:GCCCG:G	donor_gain	0.9900
1:43337923:CCAAG:C	donor_loss	0.9800
1:43337924:CAAG:C	donor_loss	0.9800
1:43337925:AAG:A	donor_loss	0.9800
1:43337926:AGGT:A	donor_loss	0.9800
1:43337927:GG:G	donor_loss	0.9800
1:43337928:GTG:G	donor_loss	0.9800
1:43337929:T:G	donor_loss	0.9800
1:43338716:TGTAG:T	donor_loss	0.9800
1:43338720:GGTA:G	donor_loss	0.9800
1:43338721:G:C	donor_loss	0.9800
1:43338722:T:A	donor_loss	0.9800
1:43339567:G:GT	donor_gain	0.9800
1:43340386:GTGGC:G	acceptor_gain	0.9800
1:43352214:A:AG	acceptor_gain	0.9800
1:43352215:G:GG	acceptor_gain	0.9800

AlphaMissense

4079 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:43340442:G:C	W303C	0.993
1:43340442:G:T	W303C	0.993
1:43338175:G:C	W52C	0.992
1:43338175:G:T	W52C	0.992
1:43348965:G:C	W477C	0.992
1:43348965:G:T	W477C	0.992
1:43346856:G:C	W410C	0.990
1:43346856:G:T	W410C	0.990
1:43346854:T:A	W410R	0.989
1:43346854:T:C	W410R	0.989
1:43348954:T:A	W474R	0.989
1:43348954:T:C	W474R	0.989
1:43348963:T:A	W477R	0.989
1:43348963:T:C	W477R	0.989
1:43346457:G:C	W331C	0.988
1:43346457:G:T	W331C	0.988
1:43348956:G:C	W474C	0.986
1:43348956:G:T	W474C	0.986
1:43348957:A:C	S475R	0.985
1:43348959:C:A	S475R	0.985
1:43348959:C:G	S475R	0.985
1:43340404:T:C	C291R	0.983
1:43340434:T:A	C301S	0.983
1:43340435:G:C	C301S	0.983
1:43348919:G:C	R462P	0.982
1:43338167:T:C	C50R	0.981
1:43340404:T:A	C291S	0.981
1:43340405:G:C	C291S	0.981
1:43346903:G:C	R426P	0.981
1:43340089:G:C	W272C	0.980

dbSNP variants (sampled 300 via entrez): RS1000219806 (1:43344336 C>A), RS1000252501 (1:43343814 G>A), RS1000275468 (1:43336903 A>G), RS1000421719 (1:43343584 C>T), RS1000458998 (1:43351031 A>T), RS1000497354 (1:43336965 G>A), RS1000500173 (1:43338034 T>C,G), RS1000593156 (1:43338277 C>T), RS1000642472 (1:43351523 G>C), RS1001244749 (1:43344611 G>C), RS1001316753 (1:43344377 CA>C), RS1001530304 (1:43338316 G>A), RS1001738234 (1:43352003 C>T), RS1001779750 (1:43344953 C>T), RS1002555403 (1:43339221 G>C)

Disease associations

OMIM: gene MIM:159530 | disease phenotypes: MIM:604498, MIM:254450, MIM:601977, MIM:134610, MIM:613688, MIM:187950

GenCC curated gene-disease

Disease	Classification	Inheritance
thrombocythemia 2	Definitive	Autosomal dominant
congenital amegakaryocytic thrombocytopenia	Definitive	Autosomal recessive
congenital amegakaryocytic thrombocytopenia 1	Strong	Autosomal recessive
hereditary isolated aplastic anemia	Supportive	Autosomal dominant
familial thrombocytosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
thrombocythemia 2	Definitive	AD
congenital amegakaryocytic thrombocytopenia 1	Definitive	AR

Mondo (13): essential thrombocythemia (MONDO:0005029), congenital amegakaryocytic thrombocytopenia (MONDO:0800451), primary myelofibrosis (MONDO:0009692), thrombocythemia 2 (MONDO:0011173), congenital amegakaryocytic thrombocytopenia 1 (MONDO:0800452), familial Mediterranean fever, autosomal dominant (MONDO:0007601), thrombocytopenia (MONDO:0002049), long QT syndrome 2 (MONDO:0013367), myelofibrosis with myeloid metaplasia (MONDO:0800305), thrombocythemia 1 (MONDO:0008554), (MONDO:0011469), (MONDO:0018340), familial thrombocytosis (MONDO:0019111)

Orphanet (6): Essential thrombocythemia (Orphanet:3318), Congenital amegakaryocytic thrombocytopenia (Orphanet:3319), Primary myelofibrosis (Orphanet:824), Familial Mediterranean fever (Orphanet:342), Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000280	Coarse facial features
HP:0000470	Short neck
HP:0000505	Visual impairment
HP:0000967	Petechiae
HP:0000975	Hyperhidrosis
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0000980	Pallor
HP:0000989	Pruritus
HP:0000995	Melanocytic nevus
HP:0001028	Hemangioma
HP:0001123	Visual field defect
HP:0001250	Seizure
HP:0001260	Dysarthria
HP:0001279	Syncope
HP:0001320	Cerebellar vermis hypoplasia
HP:0001409	Portal hypertension
HP:0001433	Hepatosplenomegaly
HP:0001442	Typified by somatic mosaicism
HP:0001658	Myocardial infarction
HP:0001671	Abnormal cardiac septum morphology
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001871	Abnormality of blood and blood-forming tissues
HP:0001872	Abnormality of thrombocytes
HP:0001873	Thrombocytopenia
HP:0001876	Pancytopenia
HP:0001892	Abnormal bleeding

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST010696_6	Cortical thickness (min-P)	3.000000e-08
GCST010697_32	Cortical surface area (min-P)	4.000000e-08
GCST010698_63	Subcortical volume (min-P)	3.000000e-09
GCST010699_87	Brain morphology (min-P)	9.000000e-14
GCST010700_24	Cortical thickness (MOSTest)	1.000000e-10
GCST010701_5	Cortical surface area (MOSTest)	1.000000e-08
GCST010702_132	Subcortical volume (MOSTest)	8.000000e-15
GCST010703_201	Brain morphology (MOSTest)	1.000000e-11
GCST90002400_27	Plateletcrit	6.000000e-24
GCST90002400_28	Plateletcrit	9.000000e-17
GCST90002402_546	Platelet count	5.000000e-13

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0007985	platelet crit
EFO:0004309	platelet count

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D055728	Primary Myelofibrosis	C15.378.190.636.765
D013920	Thrombocythemia, Essential	C15.378.100.832; C15.378.140.860.800; C15.378.190.636.860.800; C15.378.463.825
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C535982	Congenital amegakaryocytic thrombocytopenia (supp.)
C563614	Long Qt Syndrome 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1864 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 724 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2107831	LUSUTROMBOPAG	4	122
CHEMBL461101	ELTROMBOPAG	4	602

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Prolactin receptor family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
eltrombopag	Agonist	7.42	pEC50

ChEMBL bioactivities

281 potent at pChembl≥5 of 281 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.05	ED50	0.09	nM	CHEMBL3924507
8.96	ED50	1.09	nM	LUSUTROMBOPAG
8.85	ED50	1.4	nM	CHEMBL3961997
8.68	ED50	2.08	nM	CHEMBL3959282
8.52	EC50	3	nM	CHEMBL1257604
8.51	ED50	3.09	nM	CHEMBL3910159
8.22	EC50	6	nM	CHEMBL1257603
8.15	EC50	7	nM	CHEMBL429295
8.05	EC50	9	nM	CHEMBL248218
8.00	EC50	10	nM	CHEMBL455654
7.96	EC50	11	nM	CHEMBL248390
7.89	EC50	13	nM	CHEMBL249471
7.70	EC50	20	nM	CHEMBL3144775
7.68	EC50	21	nM	CHEMBL498173
7.66	EC50	22	nM	CHEMBL440231
7.66	EC50	22	nM	CHEMBL1257846
7.64	EC50	23	nM	CHEMBL248217
7.60	EC50	25	nM	CHEMBL498581
7.58	EC50	26	nM	CHEMBL496123
7.58	EC50	26	nM	CHEMBL479081
7.58	EC50	26	nM	CHEMBL1257962
7.57	EC50	27	nM	CHEMBL245795
7.55	EC50	28	nM	CHEMBL251095
7.55	EC50	28	nM	CHEMBL462874
7.54	EC50	29	nM	CHEMBL249672
7.52	EC50	30	nM	CHEMBL248428
7.51	EC50	31	nM	CHEMBL1257847
7.50	EC50	32	nM	CHEMBL247606
7.50	EC50	32	nM	CHEMBL408853
7.48	EC50	33	nM	CHEMBL247645
7.48	EC50	33	nM	CHEMBL523975
7.47	EC50	34	nM	CHEMBL516993
7.46	EC50	35	nM	CHEMBL247041
7.46	EC50	35	nM	CHEMBL477381
7.46	EC50	35	nM	CHEMBL1257724
7.43	EC50	37	nM	CHEMBL496122
7.42	EC50	38	nM	CHEMBL246847
7.42	EC50	38	nM	ELTROMBOPAG
7.40	EC50	40	nM	CHEMBL3144844
7.40	EC50	40	nM	CHEMBL3144661
7.39	EC50	41	nM	CHEMBL518285
7.38	EC50	42	nM	CHEMBL1257963
7.37	EC50	43	nM	CHEMBL245794
7.37	EC50	43	nM	CHEMBL247240
7.37	EC50	43	nM	CHEMBL461174
7.37	EC50	43	nM	CHEMBL479083
7.36	EC50	44	nM	CHEMBL1222640
7.35	EC50	45	nM	CHEMBL248389
7.34	EC50	46	nM	CHEMBL1258074
7.30	EC50	50	nM	CHEMBL459474

PubChem BioAssay actives

275 with measured affinity, of 554 total; 50 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
1-[[(E)-1-[2-(2,3-dihydro-1H-inden-5-yl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamothioyl]-2,3-dihydroindole-5-carboxylic acid	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0030	uM
1-[[(E)-1-[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamothioyl]-2,3-dihydroindole-5-carboxylic acid	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0060	uM
N-[4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-4-[[6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0070	uM
N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-4-[[6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0090	uM
1-[2,6-dichloro-4-[[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]piperidine-4-carboxylic acid	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0100	uM
N-[5-chloro-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-4-[[6-(dimethylamino)pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0110	uM
N-[3-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl]-4-[[6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0130	uM
4-[[2-(4-tert-butylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-3-hydroxynaphthalene-1-sulfonic acid	210168: Effective concentration for thrombopoietin luciferase activity was determined in BAF-3 cells	ec50	0.0200	uM
2-[[7-(4-butylphenyl)-6-fluoro-5,10-dihydroindeno[1,2-b]indol-2-yl]amino]-2-oxoacetic acid	349040: Agonist activity at human thrombopoietin receptor expressed in mouse Ba/F3 cells by kinase activation based reporter gene assay	ec50	0.0210	uM
1-[[(E)-1-[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamothioyl]-N-methyl-2,3-dihydroindole-5-carboxamide	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0220	uM
N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-4-[[6-[2-hydroxyethyl(methyl)amino]pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0220	uM
4-[[6-(azetidin-1-yl)pyrimidin-4-yl]amino]-N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0230	uM
N-[7-(4-butylphenyl)-6-fluoro-5,10-dihydroindeno[1,2-b]indol-2-yl]acetamide	349040: Agonist activity at human thrombopoietin receptor expressed in mouse Ba/F3 cells by kinase activation based reporter gene assay	ec50	0.0250	uM
1-[[(E)-1-[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamothioyl]-N-ethyl-2,3-dihydroindole-5-carboxamide	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0260	uM
6-fluoro-7-(4-fluoro-3-methylphenyl)-5,10-dihydroindeno[1,2-b]indole-2-carboxylic acid	349040: Agonist activity at human thrombopoietin receptor expressed in mouse Ba/F3 cells by kinase activation based reporter gene assay	ec50	0.0260	uM
9-(4-butylphenyl)-2-hydroxy-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	387558: Agonist activity at human thrombopoietin receptor in Ba/F3 cells assessed as activation of Stat5 response element-driven reporter gene expression	ec50	0.0260	uM
4-(pyrimidin-4-ylamino)-N-[7-(trifluoromethyl)-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazol-2-yl]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0270	uM
6-(4-carbamoylpiperidin-1-yl)-5-chloro-N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]pyridine-3-carboxamide	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0280	uM
N-[4-(3,4-difluorophenyl)-1,3-thiazol-2-yl]-4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0280	uM
N-[3-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl]-4-[[6-[[2-hydroxy-1-(hydroxyamino)ethyl]-methylamino]pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0290	uM
N-[3-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl]-4-[[6-(2-hydroxyethylamino)pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0300	uM
N-[(E)-1-[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]-5-(morpholine-4-carbonyl)-2,3-dihydroindole-1-carbothioamide	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0310	uM
N-[4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-4-(pyrimidin-4-ylamino)benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0320	uM
4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine	331576: Agonist activity at TPO receptor	ec50	0.0320	uM
N-[4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-4-(pyrimidin-4-ylamino)benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0330	uM
1-[3-chloro-5-[[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]carbamoyl]-2-pyridinyl]piperidine-4-carboxylic acid	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0330	uM
5-chloro-N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-6-(4-sulfamoylpiperidin-1-yl)pyridine-3-carboxamide	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0340	uM
1-[[(E)-1-[2-(2,3-dihydro-1H-inden-5-yl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamothioyl]-3,4-dihydro-2H-quinoline-6-carboxylic acid	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0350	uM
9-(4-fluoro-3-methylphenyl)-2-hydroxy-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	387558: Agonist activity at human thrombopoietin receptor in Ba/F3 cells assessed as activation of Stat5 response element-driven reporter gene expression	ec50	0.0350	uM
N-[4-[2-fluoro-3-(2-methylpropyl)phenyl]-1,3-thiazol-2-yl]-4-(pyrimidin-4-ylamino)benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0350	uM
6-fluoro-7-(4-propylphenyl)-5,10-dihydroindeno[1,2-b]indole-2-carboxylic acid	349040: Agonist activity at human thrombopoietin receptor expressed in mouse Ba/F3 cells by kinase activation based reporter gene assay	ec50	0.0370	uM
3-[3-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-2-hydroxyphenyl]benzoic acid	349040: Agonist activity at human thrombopoietin receptor expressed in mouse Ba/F3 cells by kinase activation based reporter gene assay	ec50	0.0380	uM
N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-4-[(6-methoxypyrimidin-4-yl)amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0380	uM
3-hydroxy-4-[[5-methyl-3-oxo-2-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]diazenyl]naphthalene-1-sulfonic acid	210168: Effective concentration for thrombopoietin luciferase activity was determined in BAF-3 cells	ec50	0.0400	uM
4-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-3-hydroxynaphthalene-1-sulfonic acid	210168: Effective concentration for thrombopoietin luciferase activity was determined in BAF-3 cells	ec50	0.0400	uM
2-hydroxy-9-(4-propoxyphenyl)-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	387558: Agonist activity at human thrombopoietin receptor in Ba/F3 cells assessed as activation of Stat5 response element-driven reporter gene expression	ec50	0.0410	uM
1-[[(E)-1-[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamoyl]-2,3-dihydroindole-5-carboxylic acid	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0420	uM
4-[[6-(dimethylamino)pyrimidin-4-yl]amino]-N-[3-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0430	uM
N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-4-[(6-methylpyrimidin-4-yl)amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0430	uM
2-hydroxy-9-(3-propoxyphenyl)-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	387558: Agonist activity at human thrombopoietin receptor in Ba/F3 cells assessed as activation of Stat5 response element-driven reporter gene expression	ec50	0.0430	uM
(4R)-1-[3-chloro-5-[[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]carbamoyl]-2-pyridinyl]-4-methylpyrrolidine-3-carboxylic acid	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0430	uM
4-[[(E)-1-[5-fluoro-2-hydroxy-1-(4-methylphenyl)indol-3-yl]ethylideneamino]carbamothioyl]benzoic acid	502110: Agonist activity at human recombinant TPO receptor expressed in mouse BaF3 cells after 24 hrs	ec50	0.0440	uM
4-[[6-(dimethylamino)pyrimidin-4-yl]amino]-N-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazol-2-yl]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0450	uM
1-[[(E)-1-[2-(2,3-dihydro-1H-inden-5-yl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamoyl]-2,3-dihydroindole-5-carboxylic acid	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0460	uM
1-[3-bromo-5-[[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]carbamoyl]-2-pyridinyl]piperidine-4-carboxylic acid	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0500	uM
4-[6-(4-butylphenyl)-7-fluoro-1H-indol-2-yl]-2-hydroxybenzoic acid	349040: Agonist activity at human thrombopoietin receptor expressed in mouse Ba/F3 cells by kinase activation based reporter gene assay	ec50	0.0510	uM
N-[4-(3-butyl-2-fluorophenyl)-1,3-thiazol-2-yl]-4-(pyrimidin-4-ylamino)benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0530	uM
4-[[6-(dimethylamino)pyrimidin-4-yl]amino]-N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0540	uM
9-(4-butylphenyl)-10-fluoro-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	387558: Agonist activity at human thrombopoietin receptor in Ba/F3 cells assessed as activation of Stat5 response element-driven reporter gene expression	ec50	0.0550	uM
1-[2-chloro-4-[[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]piperidine-4-carboxylic acid	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0560	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
Nickel	decreases expression	2
triphenyl phosphate	affects expression	1
potassium perchlorate	increases expression	1
trichostatin A	affects cotreatment, increases expression, increases reaction	1
anagrelide	decreases reaction, increases expression	1
aflatoxin B2	decreases methylation	1
hydroquinone	increases expression, increases reaction, decreases methylation, affects cotreatment	1
benzamide	affects binding, increases activity	1
midostaurin	increases expression	1
CGP 52608	increases reaction, affects binding	1
perfluoro-n-nonanoic acid	increases expression	1
perfluorohexanesulfonic acid	increases expression	1
eltrombopag	affects binding, increases activity	1
theaflavin-3,3’-digallate	affects expression	1
Decitabine	increases expression, increases reaction, affects cotreatment	1
Arsenic Trioxide	decreases expression	1
Vehicle Emissions	decreases expression	1
Benzene	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Urethane	decreases expression	1
Antirheumatic Agents	increases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression	1

ChEMBL screening assays

23 unique, capped per target: 15 functional, 7 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1019476	Functional	Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	The identification of orally bioavailable thrombopoietin agonists. — Bioorg Med Chem Lett
CHEMBL1260125	Binding	Inhibition of human TPOR expressed in human BaF3 cells	Novel indoline-1- or 3,4-dihydroquinoline-1(2H)-substituted carbothiohydrazides as TPO receptor agonists. — Bioorg Med Chem Lett
CHEMBL4623763	ADMET	Agonist activity at recombinant human c-Mpl receptor transfected in BA/F3 cells assessed as increase in cell proliferation by cell counting analysis	Discovery and structure-activity relationships study of positive allosteric modulators of the M3 muscarinic acetylcholine receptor. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 2 cancer cell line, 1 transformed cell line, 1 factor-dependent cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_6992	Marimo	Cancer cell line	Female
CVCL_A8CI	HEK-Blue TPO	Transformed cell line	Female
CVCL_D6I2	hMPL-32D	Factor-dependent cell line	Male
CVCL_E3EB	10101	Cancer cell line	Male
CVCL_JL80	M494	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03232177	PHASE4	COMPLETED	Anagre Cap. in Patients With High-Risk Essential Thrombocythemia
NCT01214915	PHASE3	COMPLETED	Effect of SPD422 on Platelet Lowering and Safety in Japanese Adults With At Risk Essential Thrombocythaemia
NCT01387763	PHASE3	COMPLETED	A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms
NCT01467661	PHASE3	COMPLETED	Long-term Safety of SPD422 in Japanese Adults With Essential Thrombocythaemia
NCT02076815	PHASE3	COMPLETED	Anagrelide Retard in Essential Thrombocythemia
NCT02611973	PHASE3	UNKNOWN	Hydroxyurea Versus Aspirin and Hydroxyurea in Essential Thrombocythemia
NCT04285086	PHASE3	ACTIVE_NOT_RECRUITING	Ropeginterferon Alfa-2b (P1101) vs. Anagrelide in Essential Thrombocythemia Patients With Hydroxyurea Resistance or Intolerance
NCT05198960	PHASE3	RECRUITING	AVAJAK: Apixaban/Rivaroxaban Versus Aspirin for Primary Prevention of Thrombo-embolic Complications in JAK2V617F-positive Myeloproliferative Neoplasms
NCT06079879	PHASE3	RECRUITING	A Study of Bomedemstat (IMG-7289/MK-3543) Compared to Best Available Therapy (BAT) in Participants With Essential Thrombocythemia and an Inadequate Response or Intolerance of Hydroxyurea (MK-3543-006)
NCT06456346	PHASE3	RECRUITING	Bomedemstat vs Hydroxyurea for Essential Thrombocythemia (MK-3543-007)
NCT00039416	PHASE2	COMPLETED	Imatinib Mesylate in Treating Patients With Myelofibrosis
NCT00047190	PHASE2	COMPLETED	Tipifarnib in Treating Patients With Myelofibrosis and Myeloid Metaplasia
NCT00089011	PHASE2	COMPLETED	Tacrolimus and Mycophenolate Mofetil in Preventing Graft-Versus-Host Disease in Patients Who Have Undergone Total-Body Irradiation With or Without Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant for Hematologic Cancer
NCT00227591	PHASE2	COMPLETED	Lenalidomide and Prednisone in Treating Patients With Myelofibrosis
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
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
NCT00489203	PHASE2	COMPLETED	Beclomethasone Dipropionate in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer
NCT00586651	PHASE2	COMPLETED	Open-Label Study of Oral CEP-701 (Lestaurtinib) in Patients With Polycythemia Vera or Essential Thrombocytosis
NCT00866762	PHASE2	UNKNOWN	A Study of the Efficacy of MK-0683 in Patients With Polycythaemia Vera and Essential Thrombocythaemia
NCT01243073	PHASE2	COMPLETED	Open Label Study to Evaluate the Activity of Imetelstat in Patients With Essential Thrombocythemia or Polycythemia Vera
NCT01384513	PHASE2	COMPLETED	A Two-Step Approach to Reduced Intensity Bone Marrow Transplant for Patients With Hematological Malignancies
NCT01998828	PHASE2	TERMINATED	Safety and Efficacy of Momelotinib in Subjects With Polycythemia Vera or Essential Thrombocythemia
NCT02124746	PHASE2	COMPLETED	Long-term Safety and Efficacy of Momelotinib in Subjects With Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis, Polycythemia Vera or Essential Thrombocythemia
NCT02311569	PHASE2	COMPLETED	Sympathicomimetic Agonist in Patients With Myeloproliferative Neoplasms With JAK2-mutation
NCT02556931	PHASE2	COMPLETED	Shorter Course Tacro After NMA, Related Donor PBSCT With High-dose Posttransplant Cy for Hard-to-Engraft Malignancies
NCT02577926	PHASE2	ACTIVE_NOT_RECRUITING	The Ruxo-BEAT Trial in Patients With High-risk Polycythemia Vera or High-risk Essential Thrombocythemia
NCT03289910	PHASE2	ACTIVE_NOT_RECRUITING	Topotecan Hydrochloride and Carboplatin With or Without Veliparib in Treating Advanced Myeloproliferative Disorders and Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia
NCT04243122	PHASE2	COMPLETED	Assessing Feasibility of Thromboprophylaxis With Apixaban in JAK2-positive Myeloproliferative Neoplasm Patients
NCT04254978	PHASE2	COMPLETED	Study of Bomedemstat in Participants With Essential Thrombocythemia (IMG-7289-CTP-201/MK-3543-003)
NCT04262141	PHASE2	ACTIVE_NOT_RECRUITING	IMG-7289 in Patients With Essential Thrombocythemia (ET) or Polycythemia Vera (PV)
NCT04282187	PHASE2	RECRUITING	Decitabine With Ruxolitinib, Fedratinib or Pacritinib for the Treatment of Accelerated/Blast Phase Myeloproliferative Neoplasms
NCT04644211	PHASE2	RECRUITING	Ruxolitinib in Thrombocythemia and Polycythemia Vera
NCT05031897	PHASE2	RECRUITING	Two Step Haplo With Radiation Conditioning
NCT05482971	PHASE2	ACTIVE_NOT_RECRUITING	A Single-arm, Multicenter Study to Assess the Efficacy, Safety, and Tolerability of P1101 in Adults With ET
NCT06063486	PHASE2	RECRUITING	Curcumin to Improve Inflammation and Symptoms in Patients With Clonal Cytopenia of Undetermined Significance, Low Risk Myelodysplastic Syndrome, and Myeloproliferative Neoplasms
NCT06541249	PHASE2	RECRUITING	MethoTRExATE in MyelOpRolifErative Neoplasms (TREATMORE) Trial
NCT06552429	PHASE2	RECRUITING	Peginterferon α-2b Injection for Hydroxyurea Resistant or Intolerant ET
NCT06661915	PHASE2	SUSPENDED	A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)
NCT00301834	PHASE2	COMPLETED	Alemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies