Primary myelofibrosis

Summary

Primary myelofibrosis (MONDO:0009692) is a disease with 6 cohort genes and 173 clinical trials. The dominant Reactome pathway is Signaling by SCF-KIT (3 cohort genes). Top therapeutic interventions include ruxolitinib, momelotinib, and pacritinib.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 6
• ClinVar variants: 78
• Phenotypes (HPO): 36
• Clinical trials: 173

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	1	Europe	Validated
Point prevalence	1-9 / 100 000	3	Europe	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0005561	Abnormality of bone marrow cell morphology	Very frequent (80-99%)
HP:0000980	Pallor	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001871	Abnormality of blood and blood-forming tissues	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0012143	Abnormal megakaryocyte morphology	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0025142	Constitutional symptom	Frequent (30-79%)
HP:0000967	Petechiae	Occasional (5-29%)
HP:0000979	Purpura	Occasional (5-29%)
HP:0001409	Portal hypertension	Occasional (5-29%)
HP:0001876	Pancytopenia	Occasional (5-29%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0001894	Thrombocytosis	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0001974	Leukocytosis	Occasional (5-29%)
HP:0001977	Abnormal thrombosis	Occasional (5-29%)
HP:0001978	Extramedullary hematopoiesis	Occasional (5-29%)
HP:0002039	Anorexia	Occasional (5-29%)
HP:0002716	Lymphadenopathy	Occasional (5-29%)
HP:0003388	Easy fatigability	Occasional (5-29%)
HP:0004420	Arterial thrombosis	Occasional (5-29%)
HP:0004447	Poikilocytosis	Occasional (5-29%)
HP:0004936	Venous thrombosis	Occasional (5-29%)
HP:0011134	Low-grade fever	Occasional (5-29%)
HP:0030157	Flank pain	Occasional (5-29%)
HP:0031020	Bone marrow hypercellularity	Occasional (5-29%)
HP:0031364	Ecchymosis	Occasional (5-29%)
HP:0030057	Autoimmune antibody positivity	Excluded (0%)
HP:0001028	Hemangioma	Very rare (<1-4%)
HP:0004326	Cachexia	Very rare (<1-4%)
HP:0004377	Hematological neoplasm	Very rare (<1-4%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	primary myelofibrosis
Mondo ID	MONDO:0009692
EFO	EFO:0002430
MeSH	D055728
OMIM	254450
Orphanet	824
DOID	DOID:4971
ICD-10-CM	D47.4
ICD-11	1407285327, 336704235
NCIT	C2862
UMLS	C0001815
MedGen	7929
GARD	0008618
NORD	1611
Is cancer (heuristic)	no

Also known as: Agnogenic myeloid metaplasia · AMM · chronic idiopathic myelofibrosis · CIMF · idiopathic bone marrow fibrosis · idiopathic myelofibrosis · myelofibrosis with myeloid metaplasia · myelofibrosis with myeloid metaplasia, somatic · myelofibrosis, somatic · myeloid metaplasia · myelosclerosis with myeloid metaplasia · osteomyelofibrosis · primary myelofibrosis

Data availability: 78 ClinVar variants · 9 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › aplastic anemia › acquired aplastic anemia › primary myelofibrosis

Related subtypes (2): primary acquired red cell aplasia, paroxysmal nocturnal hemoglobinuria

Subtypes (4): cellular phase chronic idiopathic myelofibrosis, familial myelofibrosis, panostotic fibrous dysplasia, myelofibrosis with myeloid metaplasia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

78 retrieved; paginated sample, class counts are floors:

23 likely pathogenic, 17 pathogenic/likely pathogenic, 16 uncertain significance, 9 pathogenic, 9 conflicting classifications of pathogenicity, 3 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028735	NM_004343.4(CALR):c.1154_1155insTTGTC (p.Lys385fs)	CALR	Pathogenic	criteria provided, multiple submitters, no conflicts
97006	NM_004343.3(CALR):c.1092_1143del52 (p.Leu367Thrfs)	CALR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14662	NM_004972.4(JAK2):c.1849G>T (p.Val617Phe)	INSL6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069689	NM_005373.3(MPL):c.273C>A (p.Tyr91Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069872	NM_005373.3(MPL):c.230del (p.Cys77fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075094	NM_005373.3(MPL):c.308del (p.Leu103fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1301356	NM_005373.3(MPL):c.367C>T (p.Arg123Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
134822	NM_005373.3(MPL):c.235_236del (p.Leu79fs)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
135563	NM_005373.3(MPL):c.79+2T>A	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14154	NM_005373.3(MPL):c.556C>T (p.Gln186Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
14156	NM_005373.3(MPL):c.769C>T (p.Arg257Cys)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14157	NM_005373.3(MPL):c.1904C>T (p.Pro635Leu)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14158	NM_005373.3(MPL):c.305G>C (p.Arg102Pro)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
1453832	NM_005373.3(MPL):c.1431G>A (p.Trp477Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1504060	NM_005373.3(MPL):c.460T>C (p.Trp154Arg)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265248	NM_005373.3(MPL):c.317C>T (p.Pro106Leu)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265249	NM_005373.3(MPL):c.378del (p.Phe126fs)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
2928056	NM_005373.3(MPL):c.1033C>T (p.Gln345Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3340285	NM_005373.3(MPL):c.1545G>A (p.Trp515Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371574	NM_005373.3(MPL):c.127C>T (p.Arg43Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
435886	NM_005373.3(MPL):c.972del (p.Arg325fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
458369	NM_005373.3(MPL):c.1744_1745del (p.Leu582fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631607	NM_005373.3(MPL):c.1774C>T (p.Arg592Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632897	NM_005373.3(MPL):c.1653+1del	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
956954	NM_005373.3(MPL):c.268C>T (p.Arg90Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
30444	NM_005475.3(SH2B3):c.603_607del (p.Arg202fs)	SH2B3	Pathogenic	no assertion criteria provided
208237	NC_000014.9:g.95696766_96390792dup	LOC130056392	Likely pathogenic	criteria provided, single submitter
1379348	NM_005373.3(MPL):c.407C>A (p.Pro136His)	MPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1492963	NM_005373.3(MPL):c.1566-1G>A	MPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1523230	NM_005373.3(MPL):c.1166-1G>C	MPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 17 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SRC	Orphanet:480851	Hereditary thrombocytopenia with early-onset myelofibrosis
CALR	Orphanet:131	Budd-Chiari syndrome
CALR	Orphanet:3318	Essential thrombocythemia
CALR	Orphanet:824	Primary myelofibrosis
SH2B3	Orphanet:3318	Essential thrombocythemia
SH2B3	Orphanet:391366	Growth retardation-mild developmental delay-chronic hepatitis syndrome
JAK2	Orphanet:131	Budd-Chiari syndrome
JAK2	Orphanet:3318	Essential thrombocythemia
JAK2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
JAK2	Orphanet:71493	Familial thrombocytosis
JAK2	Orphanet:729	Polycythemia vera
JAK2	Orphanet:824	Primary myelofibrosis
MPL	Orphanet:3318	Essential thrombocythemia
MPL	Orphanet:3319	Congenital amegakaryocytic thrombocytopenia
MPL	Orphanet:397692	Hereditary isolated aplastic anemia
MPL	Orphanet:71493	Familial thrombocytosis
MPL	Orphanet:824	Primary myelofibrosis

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SRC	HGNC:11283	ENSG00000197122	P12931	Proto-oncogene tyrosine-protein kinase Src	clinvar
CALR	HGNC:1455	ENSG00000179218	P27797	Calreticulin	clinvar
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	clinvar
INSL6	HGNC:6089	ENSG00000120210	Q9Y581	Insulin-like peptide INSL6	clinvar
JAK2	HGNC:6192	ENSG00000096968	O60674	Tyrosine-protein kinase JAK2	clinvar
MPL	HGNC:7217	ENSG00000117400	P40238	Thrombopoietin receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SRC	Proto-oncogene tyrosine-protein kinase Src	Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G…
CALR	Calreticulin	Calcium-binding chaperone that promotes folding, oligomeric assembly and quality control in the endoplasmic reticulum (ER) via the calreticulin/calnexin cycle.
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
INSL6	Insulin-like peptide INSL6	May have a role in sperm development and fertilization.
JAK2	Tyrosine-protein kinase JAK2	Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications.
MPL	Thrombopoietin receptor	Receptor for thrombopoietin that regulates hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	2	9.2×	0.071
Antibody/Immunoglobulin	1	4.9×	0.377
Scaffold/PPI	1	2.9×	0.401
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SRC	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
CALR	Other/Unknown	no		Calret/calnex, Calreticulin/calnexin_P_dom_sf, Calreticulin
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
INSL6	Other/Unknown	no		Insulin-like, Insulin-like_pep_6, Insulin_CS
JAK2	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2
MPL	Antibody/Immunoglobulin	yes		Long_hematopoietin_rcpt_CS, FN3_dom, Ig-like_fold

Expression context

Cohort genes with no expression data: 0.

6 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	3
mononuclear cell	2
male germ line stem cell (sensu Vertebrata) in testis	2
body of stomach	1
gall bladder	1
rectum	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
stromal cell of endometrium	1
leukocyte	1
left testis	1
right testis	1
blood vessel layer	1
calcaneal tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SRC	236	ubiquitous	marker	body of stomach, gall bladder, rectum
CALR	289	ubiquitous	marker	stromal cell of endometrium, left lobe of thyroid gland, right lobe of thyroid gland
SH2B3	260	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
INSL6	152	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, left testis, right testis
JAK2	272	ubiquitous	marker	calcaneal tendon, monocyte, blood vessel layer
MPL	166	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, mononuclear cell, monocyte

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SRC	11,608
JAK2	6,197
CALR	6,185
SH2B3	1,617
MPL	1,039
INSL6	509

Intra-cohort edges

A	B	Sources
CALR	MPL	string_interaction
JAK2	MPL	biogrid_interaction, intact, string_interaction
JAK2	SH2B3	biogrid_interaction, string_interaction
MPL	SH2B3	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
JAK2	O60674	164
SRC	P12931	79
CALR	P27797	10
MPL	P40238	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SH2B3	Q9UQQ2	63.45
INSL6	Q9Y581	54.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 190. Enrichment computed across 6 evidence-associated genes (5 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by SCF-KIT	3	149.0×	1e-04	SRC, SH2B3, JAK2
Regulation of KIT signaling	2	240.4×	0.002	SRC, SH2B3
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	2	207.6×	0.002	SRC, JAK2
Platelet Aggregation (Plug Formation)	2	175.7×	0.002	SRC, MPL
Signaling by RAS mutants	2	169.2×	0.002	SRC, JAK2
Signaling by Receptor Tyrosine Kinases	3	31.0×	0.002	SRC, SH2B3, JAK2
RAF activation	2	134.3×	0.002	SRC, JAK2
Signaling by RAF1 mutants	2	111.4×	0.002	SRC, JAK2
Signaling by moderate kinase activity BRAF mutants	2	101.5×	0.002	SRC, JAK2
Paradoxical activation of RAF signaling by kinase inactive BRAF	2	101.5×	0.002	SRC, JAK2
Signaling downstream of RAS mutants	2	101.5×	0.002	SRC, JAK2
Oncogenic MAPK signaling	2	99.3×	0.002	SRC, JAK2
Cytokine Signaling in Immune system	3	24.5×	0.002	SRC, SH2B3, JAK2
Immune System	4	10.4×	0.002	SRC, CALR, SH2B3, JAK2
Cyclin D associated events in G1	2	93.2×	0.002	SRC, JAK2
Hemostasis	3	21.6×	0.002	SRC, SH2B3, JAK2
Signaling by BRAF and RAF1 fusions	2	68.2×	0.004	SRC, JAK2
MAPK1/MAPK3 signaling	2	52.5×	0.006	SRC, JAK2
Infectious disease	3	14.9×	0.006	SRC, CALR, JAK2
Virus Assembly and Release	1	1142.0×	0.008	CALR
Assembly of Viral Components at the Budding Site	1	1142.0×	0.008	CALR
MAPK family signaling cascades	2	41.1×	0.008	SRC, JAK2
Regulation of gap junction activity	1	761.3×	0.011	SRC
Scavenging by Class F Receptors	1	380.7×	0.017	CALR
ATF6 (ATF6-alpha) activates chaperones	1	380.7×	0.017	CALR
Activated NTRK2 signals through FYN	1	380.7×	0.017	SRC
Activated NTRK3 signals through PI3K	1	380.7×	0.017	SRC
Factors involved in megakaryocyte development and platelet production	2	26.6×	0.017	SH2B3, JAK2
RAF/MAP kinase cascade	2	24.4×	0.017	SRC, JAK2
Signaling by NTRK2 (TRKB)	1	326.3×	0.018	SRC

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
thrombopoietin-mediated signaling pathway	3	1263.9×	2e-07	SH2B3, JAK2, MPL
monocyte homeostasis	2	2246.9×	2e-05	SH2B3, MPL
cellular response to interleukin-3	2	1123.5×	8e-05	SH2B3, JAK2
neutrophil homeostasis	2	612.8×	2e-04	SH2B3, MPL
interleukin-6-mediated signaling pathway	2	449.4×	3e-04	SRC, JAK2
nuclear receptor-mediated mineralocorticoid signaling pathway	1	3370.4×	0.006	JAK2
symbiont-induced defense-related programmed cell death	1	3370.4×	0.006	JAK2
interleukin-35-mediated signaling pathway	1	3370.4×	0.006	JAK2
basophil homeostasis	1	3370.4×	0.006	MPL
regulation of caveolin-mediated endocytosis	1	3370.4×	0.006	SRC
cellular response to virus	2	80.2×	0.006	CALR, JAK2
intracellular signal transduction	3	22.9×	0.006	SRC, SH2B3, JAK2
regulation of toll-like receptor 3 signaling pathway	1	1685.2×	0.007	SRC
positive regulation of dephosphorylation	1	1685.2×	0.007	SRC
response to interleukin-12	1	1685.2×	0.007	JAK2
negative regulation of Kit signaling pathway	1	1685.2×	0.007	SH2B3
positive regulation of growth factor dependent skeletal muscle satellite cell proliferation	1	1685.2×	0.007	JAK2
positive regulation of platelet formation	1	1685.2×	0.007	MPL
regulation of postsynapse to nucleus signaling pathway	1	1685.2×	0.007	JAK2
positive regulation of growth hormone receptor signaling pathway	1	1123.5×	0.009	JAK2
response to biphenyl	1	1123.5×	0.009	CALR
eosinophil homeostasis	1	1123.5×	0.009	MPL
positive regulation of platelet-derived growth factor receptor-beta signaling pathway	1	1123.5×	0.009	SRC
negative regulation of intracellular steroid hormone receptor signaling pathway	1	842.6×	0.009	CALR
collagen-activated signaling pathway	1	842.6×	0.009	JAK2
granulocyte-macrophage colony-stimulating factor signaling pathway	1	842.6×	0.009	JAK2
nuclear receptor-mediated glucocorticoid signaling pathway	1	842.6×	0.009	CALR
activation of Janus kinase activity	1	842.6×	0.009	JAK2
regulation of cell projection assembly	1	842.6×	0.009	SRC
obsolete sequestering of calcium ion	1	674.1×	0.009	CALR

Therapeutics

Drugs indicated for this disease

0 approved, 10 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Fedratinib	Phase 3 (in late-stage trials)
Hydroxyurea	Phase 3 (in late-stage trials)
Imetelstat	Phase 3 (in late-stage trials)
Momelotinib	Phase 3 (in late-stage trials)
Navitoclax	Phase 3 (in late-stage trials)
PEGINTERFERON ALFA-2A	Phase 3 (in late-stage trials)
PEGINTERFERON ALFA-2B	Phase 3 (in late-stage trials)
Pomalidomide	Phase 3 (in late-stage trials)
Ruxolitinib	Phase 3 (in late-stage trials)
Selinexor	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Azacitidine, Bevacizumab, Bomedemstat, Busulfan, Decitabine, Fludarabine, Fludarabine Phosphate, Fostamatinib, Itacitinib, Lenalidomide, Melphalan, Methotrexate, Mycophenolate Mofetil, Navtemadlin, Pacritinib, Plitidepsin, Prednisone, ROPEGINTERFERON ALFA-2B, Ridaforolimus, Sotatercept, Tacrolimus Anhydrous, Thalidomide, Thiotepa, Tipifarnib, Zinpentraxin Alfa.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 3

Druggability breadth: 4 of 6 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SRC	PONATINIB
JAK2	FEDRATINIB
MPL	LUSUTROMBOPAG

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SRC	103	4
JAK2	100	4
MPL	2	4
CALR	0	0
SH2B3	0	0
INSL6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	JAK2, SRC
AFATINIB	4	SRC
FEDRATINIB	4	JAK2, SRC
TIVOZANIB	4	SRC
SORAFENIB	4	SRC
DASATINIB ANHYDROUS	4	SRC
NICLOSAMIDE	4	JAK2, SRC
NERATINIB	4	SRC
INFIGRATINIB PHOSPHATE	4	JAK2, SRC
INFIGRATINIB	4	JAK2, SRC
IBRUTINIB	4	SRC
ENTRECTINIB	4	JAK2, SRC
CABOZANTINIB	4	SRC
DACOMITINIB ANHYDROUS	4	SRC
CERITINIB	4	JAK2, SRC
VANDETANIB	4	SRC
NILOTINIB	4	SRC
BOSUTINIB	4	JAK2, SRC
BRIGATINIB	4	JAK2, SRC
REPOTRECTINIB	4	JAK2, SRC
PAZOPANIB	4	JAK2, SRC
NINTEDANIB	4	JAK2, SRC
SUNITINIB	4	JAK2, SRC
DASATINIB	4	JAK2, SRC
ERLOTINIB	4	JAK2, SRC
LAPATINIB	4	SRC
TIRBANIBULIN	4	SRC
CRIZOTINIB	4	JAK2, SRC
MIDOSTAURIN	4	JAK2, SRC
ADENOSINE PHOSPHATE	4	SRC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
JAK2	2,018	Binding:1911, Functional:51, ADMET:48, Unclassified:4, Toxicity:4
SRC	1,917	Binding:1858, Functional:43, ADMET:16
MPL	23	Functional:15, Binding:7, ADMET:1
CALR	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SRC	2.7.10.2	non-specific protein-tyrosine kinase
JAK2	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SRC	1,917
JAK2	2,018

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

27 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	JAK2, SRC
AFATINIB	4	SRC
TIVOZANIB	4	SRC
SORAFENIB	4	SRC
NICLOSAMIDE	4	JAK2, SRC
NERATINIB	4	SRC
INFIGRATINIB PHOSPHATE	4	JAK2, SRC
INFIGRATINIB	4	JAK2, SRC
IBRUTINIB	4	SRC
ENTRECTINIB	4	JAK2, SRC
CABOZANTINIB	4	SRC
CERITINIB	4	JAK2, SRC
VANDETANIB	4	SRC
NILOTINIB	4	SRC
BOSUTINIB	4	JAK2, SRC
BRIGATINIB	4	JAK2, SRC
REPOTRECTINIB	4	JAK2, SRC
PAZOPANIB	4	JAK2, SRC
NINTEDANIB	4	JAK2, SRC
SUNITINIB	4	JAK2, SRC
DASATINIB	4	JAK2, SRC
ERLOTINIB	4	JAK2, SRC
LAPATINIB	4	SRC
TIRBANIBULIN	4	SRC
CRIZOTINIB	4	JAK2, SRC
MIDOSTAURIN	4	JAK2, SRC
ADENOSINE PHOSPHATE	4	SRC

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SRC, JAK2, MPL
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	CALR, SH2B3, INSL6

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SH2B3	0	JAK2
CALR	1	—
INSL6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 173.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	66
Not specified	35
PHASE1	30
PHASE3	20
PHASE1/PHASE2	16
PHASE4	2
PHASE2/PHASE3	2
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02386800	PHASE4	ACTIVE_NOT_RECRUITING	CINC424A2X01B Rollover Protocol
NCT01558739	PHASE4	COMPLETED	Exploratory Phase II Study of INC424 Patients With Primary Myelofibrosis (PMF) or Post Polycythaemia Myelofibrosis (PPV MF) or Post Essential Thrombocythaemia Myelofibrosis (PET-MF)
NCT03165734	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study of Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis
NCT04603495	PHASE3	ACTIVE_NOT_RECRUITING	Phase 3 Study of Pelabresib (CPI-0610) in Myelofibrosis (MF) (MANIFEST-2)
NCT04717414	PHASE3	ACTIVE_NOT_RECRUITING	An Efficacy and Safety Study of Luspatercept (ACE-536) Versus Placebo in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis on Concomitant JAK2 Inhibitor Therapy and Who Require Red Blood Cell Transfusions
NCT06351631	PHASE3	RECRUITING	A Study to Evaluate Safety and Efficacy of Bomedemstat (MK-3543-017)
NCT06468033	PHASE3	RECRUITING	P1101 in Treating Patients With Early PMF or Overt PMF at Low or Intermediate-1 Risk
NCT06479135	PHASE3	RECRUITING	Study of Navtemadlin add-on to Ruxolitinib in JAK Inhibitor-Naïve Patients With Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib
NCT07357727	PHASE3	RECRUITING	A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF)
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
NCT01178281	PHASE3	COMPLETED	Study of Pomalidomide in Persons With Myeloproliferative-Neoplasm-Associated Myelofibrosis and RBC-Transfusion-Dependence
NCT01387763	PHASE3	COMPLETED	A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms
NCT01428635	PHASE2/PHASE3	COMPLETED	Eltrombopag Olamine in Treating Thrombocytopenia in Patients With Chronic Myeloid Leukemia or Myelofibrosis Receiving Tyrosine Kinase Therapy
NCT01773187	PHASE3	TERMINATED	Pacritinib Versus Best Available Therapy to Treat Myelofibrosis
NCT01969838	PHASE3	COMPLETED	Momelotinib Versus Ruxolitinib in Subjects With Myelofibrosis
NCT02055781	PHASE3	TERMINATED	Pacritinib Versus Best Available Therapy to Treat Patients With Myelofibrosis and Thrombocytopenia
NCT02087059	PHASE3	COMPLETED	A Clinical Study of Ruxolitinib in Patients With Primary Myelofibrosis (PM), Post-polycythemia Vera (PV) Myelofibrosis, or Post-essential Thrombocythemia (ET) Myelofibrosis
NCT02101268	PHASE3	COMPLETED	Efficacy of Momelotinib Versus Best Available Therapy in Anemic or Thrombocytopenic Subjects With Primary Myelofibrosis (MF), Post-polycythemia Vera MF, or Post-essential Thrombocythemia MF
NCT03662126	PHASE2/PHASE3	UNKNOWN	KRT-232 Versus Best Available Therapy for the Treatment of Subjects With Myelofibrosis Who Are Relapsed or Refractory to JAK Inhibitor Treatment
NCT03755518	PHASE3	TERMINATED	A Trial of Fedratinib in Subjects With DIPSS, Intermediate or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis and Previously Treated With Ruxolitinib
NCT03952039	PHASE3	COMPLETED	An Efficacy and Safety Study of Fedratinib Compared to Best Available Therapy in Subjects With DIPSS-intermediate or High-risk Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis and Previously Treated With Ruxolitinib
NCT04173494	PHASE3	COMPLETED	A Study of Momelotinib Versus Danazol in Symptomatic and Anemic Myelofibrosis Participants (MOMENTUM)
NCT04551053	PHASE3	TERMINATED	To Evaluate Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis Who Have Suboptimal Response to Ruxolitinib (LIMBER-304)
NCT04551066	PHASE3	TERMINATED	To Evaluate the Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis (LIMBER-313)
NCT00095784	PHASE2	ACTIVE_NOT_RECRUITING	Decitabine in Treating Patients With Myelofibrosis
NCT03441113	PHASE2	ACTIVE_NOT_RECRUITING	Extended Access of Momelotinib in Adults With Myelofibrosis
NCT04282187	PHASE2	RECRUITING	Decitabine With Ruxolitinib, Fedratinib or Pacritinib for the Treatment of Accelerated/Blast Phase Myeloproliferative Neoplasms
NCT04370301	PHASE2	RECRUITING	Reduced Intensity Haploidentical Transplantation for the Treatment of Primary or Secondary Myelofibrosis
NCT04384692	PHASE2	ACTIVE_NOT_RECRUITING	Peritransplant Ruxolitinib for Patients With Primary and Secondary Myelofibrosis
NCT04446650	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of Fedratinib in Japanese Subjects With DIPSS (Dynamic International Prognostic Scoring System)- Intermediate or High-risk Primary Myelofibrosis (PMF), Post-polycythemia Vera Myelofibrosis (Post-PV MF), or Post-essential Thrombocythemia Myelofibrosis (Post-ET MF)
NCT04517851	PHASE2	ACTIVE_NOT_RECRUITING	Elotuzumab for the Treatment of JAK2-Mutated Myelofibrosis
NCT05280509	PHASE1/PHASE2	RECRUITING	Study of TL-895 Combined With Ruxolitinib in JAKi Treatment-Naïve MF Subjects and Subjects With MF Who Have a Suboptimal Response to Ruxolitinib
NCT05320198	PHASE1/PHASE2	RECRUITING	Study of DISC-0974 (RALLY-MF) in Participants With Myelofibrosis or Myelodysplastic Syndrome and Anemia
NCT05364762	PHASE2	ACTIVE_NOT_RECRUITING	Adding Itacitinib to Cyclophosphamide and Tacrolimus for the Prevention of Graft Versus Host Disease in Patients Undergoing Hematopoietic Stem Cell Transplants
NCT05467800	PHASE2	ACTIVE_NOT_RECRUITING	Study of Canakinumab in Patients With Myelofibrosis
NCT06327100	PHASE1/PHASE2	RECRUITING	Open Label Phase 1/2 Study of Tasquinimod in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), or Post-Essential Thrombocytosis Myelofibrosis (Post-ET MF)
NCT06517875	PHASE2	RECRUITING	Study of Momelotinib in Combination With Luspatercept in Participants With Transfusion Dependent Myelofibrosis
NCT06770842	PHASE2	RECRUITING	Ropeginterferon Alfa 2b Plus Ruxolitinib for Myelofibrosis
NCT07228624	PHASE2	RECRUITING	Ruxolitinib Before, During and After Hematopoietic Cell Transplant in Older Patients With Myelofibrosis and Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Syndromes
NCT00015821	PHASE2	COMPLETED	Thalidomide in Treating Patients With Myelofibrosis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RUXOLITINIB	4	39
MOMELOTINIB	4	10
PACRITINIB	4	7
FEDRATINIB	4	6
METHOTREXATE	4	6
LUSPATERCEPT	4	4
ELTROMBOPAG	4	3
PANOBINOSTAT	4	3
POMALIDOMIDE	4	3
DANAZOL	4	2
DASATINIB ANHYDROUS	4	2
DEFERASIROX	4	2
DURVALUMAB	4	2
IMATINIB MESYLATE	4	2
PALIFERMIN	4	2
ROPEGINTERFERON ALFA-2B	4	2
SONIDEGIB	4	2
BECLOMETHASONE DIPROPIONATE	4	1
BELINOSTAT	4	1
CANAKINUMAB	4	1
CEDAZURIDINE	4	1
CEFEPIME HYDROCHLORIDE	4	1
COBIMETINIB	4	1
COPANLISIB	4	1
DACOMITINIB	4	1
DACOMITINIB ANHYDROUS	4	1
DAROLUTAMIDE	4	1
DECITABINE	4	1
ELOTUZUMAB	4	1
ENASIDENIB	4	1