Myelofibrosis

Summary

Myelofibrosis (MONDO:0044903) is a disease with 3 cohort genes and 290 clinical trials. Molecularly, NTRK2 A203T confers sensitivity to Entrectinib + Larotrectinib in Myelofibrosis (CIViC Level D). Top therapeutic interventions include ruxolitinib, methotrexate, and pacritinib.

At a glance

• Cohort genes: 3
• Clinical trials: 290
• Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myelofibrosis
Mondo ID	MONDO:0044903
NCIT	C3248
UMLS	C0026987
MedGen	10146
GARD	0025920
Is cancer (heuristic)	no

Also known as: myelofibrosis

Data availability: 14 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › hematopoietic and lymphoid system neoplasm › hematopoietic and lymphoid cell neoplasm › myeloid neoplasm › myeloproliferative neoplasm › myelofibrosis

Related subtypes (12): myeloid leukemia, essential thrombocythemia, myelodysplastic/myeloproliferative neoplasm, therapy-related myeloid neoplasm, transient myeloproliferative syndrome, primary myelofibrosis, myeloproliferative disease, autosomal recessive, thrombocytopenia 6, chronic eosinophilic leukemia, chronic neutrophilic leukemia, myeloproliferative neoplasm, unclassifiable, erythroid neoplasm

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CALR	Orphanet:131	Budd-Chiari syndrome
CALR	Orphanet:3318	Essential thrombocythemia
CALR	Orphanet:824	Primary myelofibrosis
ASXL1	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
ASXL1	Orphanet:97297	Bohring-Opitz syndrome
ASXL1	Orphanet:98823	Chronic myelomonocytic leukemia
ASXL1	Orphanet:98849	Systemic mastocytosis with associated hematologic neoplasm
ASXL1	Orphanet:98850	Aggressive systemic mastocytosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
U2AF1	HGNC:12453	ENSG00000160201	Q01081	Splicing factor U2AF 35 kDa subunit	civic_evidence
CALR	HGNC:1455	ENSG00000179218	P27797	Calreticulin	civic_evidence
ASXL1	HGNC:18318	ENSG00000171456	Q8IXJ9	Polycomb group protein ASXL1	civic_evidence

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
U2AF1	Splicing factor U2AF 35 kDa subunit	Plays a critical role in both constitutive and enhancer-dependent splicing by mediating protein-protein interactions and protein-RNA interactions required for accurate 3’-splice site selection.
CALR	Calreticulin	Calcium-binding chaperone that promotes folding, oligomeric assembly and quality control in the endoplasmic reticulum (ER) via the calreticulin/calnexin cycle.
ASXL1	Polycomb group protein ASXL1	Probable Polycomb group (PcG) protein involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor gamma (PPARG).

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
U2AF1	Transcription factor	no		RRM_dom, Znf_CCCH, RRM_euk-type
CALR	Other/Unknown	no		Calret/calnex, Calreticulin/calnexin_P_dom_sf, Calreticulin
ASXL1	Other/Unknown	no		Asxl_HARE-HTH, ASX/ASX-like, ASX-like_PHD

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
bone marrow	1
left uterine tube	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
stromal cell of endometrium	1
adrenal tissue	1
sperm	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
U2AF1	134	ubiquitous	marker	adenohypophysis, left uterine tube, bone marrow
CALR	289	ubiquitous	marker	stromal cell of endometrium, left lobe of thyroid gland, right lobe of thyroid gland
ASXL1	294	ubiquitous	marker	sural nerve, sperm, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CALR	6,185
U2AF1	2,853
ASXL1	2,816

Intra-cohort edges

A	B	Sources
ASXL1	U2AF1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CALR	P27797	10
ASXL1	Q8IXJ9	4
U2AF1	Q01081	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Virus Assembly and Release	1	1903.3×	0.009	CALR
Assembly of Viral Components at the Budding Site	1	1903.3×	0.009	CALR
Scavenging by Class F Receptors	1	634.4×	0.013	CALR
ATF6 (ATF6-alpha) activates chaperones	1	634.4×	0.013	CALR
ATF6 (ATF6-alpha) activates chaperone genes	1	380.7×	0.018	CALR
Calnexin/calreticulin cycle	1	237.9×	0.023	CALR
Scavenging by Class A Receptors	1	200.3×	0.023	CALR
Binding and Uptake of Ligands by Scavenger Receptors	1	181.3×	0.023	CALR
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	141.0×	0.024	CALR
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	131.3×	0.024	CALR
Unfolded Protein Response (UPR)	1	119.0×	0.024	CALR
Post-translational protein modification	2	12.8×	0.024	CALR, ASXL1
Antigen processing-Cross presentation	1	105.7×	0.025	CALR
Maturation of DENV proteins	1	70.5×	0.034	CALR
mRNA 3’-end processing	1	65.6×	0.034	U2AF1
Influenza Infection	1	58.6×	0.036	CALR
Transport of Mature mRNA derived from an Intron-Containing Transcript	1	50.8×	0.037	U2AF1
Metabolism of proteins	2	8.2×	0.037	CALR, ASXL1
ER-Phagosome pathway	1	43.3×	0.039	CALR
Deubiquitination	1	41.4×	0.039	ASXL1
UCH proteinases	1	41.4×	0.039	ASXL1
mRNA Polyadenylation	1	29.3×	0.052	U2AF1
Class I MHC mediated antigen processing & presentation	1	23.4×	0.062	CALR
Asparagine N-linked glycosylation	1	20.0×	0.070	CALR
mRNA Splicing - Major Pathway	1	18.2×	0.073	U2AF1
Dengue Virus-Host Interactions	1	15.2×	0.084	U2AF1
Cellular responses to stress	1	12.3×	0.100	CALR
Vesicle-mediated transport	1	11.6×	0.102	CALR
Cellular responses to stimuli	1	10.5×	0.107	CALR
Viral Infection Pathways	1	10.3×	0.107	CALR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of kidney size	1	2808.7×	0.007	ASXL1
response to biphenyl	1	1872.4×	0.007	CALR
negative regulation of intracellular steroid hormone receptor signaling pathway	1	1404.3×	0.007	CALR
nuclear receptor-mediated glucocorticoid signaling pathway	1	1404.3×	0.007	CALR
positive regulation of retinoic acid receptor signaling pathway	1	1123.5×	0.007	ASXL1
obsolete sequestering of calcium ion	1	1123.5×	0.007	CALR
peptide antigen assembly with MHC class I protein complex	1	936.2×	0.007	CALR
negative regulation of peroxisome proliferator activated receptor signaling pathway	1	936.2×	0.007	ASXL1
regulation of meiotic nuclear division	1	802.5×	0.007	CALR
negative regulation of trophoblast cell migration	1	802.5×	0.007	CALR
response to glycoside	1	802.5×	0.007	CALR
lung saccule development	1	702.2×	0.007	ASXL1
positive regulation of dendritic cell chemotaxis	1	702.2×	0.007	CALR
negative regulation of retinoic acid receptor signaling pathway	1	510.7×	0.007	CALR
bone marrow development	1	510.7×	0.007	ASXL1
podocyte development	1	510.7×	0.007	ASXL1
protein folding in endoplasmic reticulum	1	468.1×	0.008	CALR
cellular response to electrical stimulus	1	432.1×	0.008	CALR
cellular response to lithium ion	1	374.5×	0.008	CALR
response to peptide	1	374.5×	0.008	CALR
homeostasis of number of cells	1	224.7×	0.012	ASXL1
cardiac muscle cell differentiation	1	224.7×	0.012	CALR
cortical actin cytoskeleton organization	1	200.6×	0.013	CALR
protein export from nucleus	1	170.2×	0.015	CALR
response to testosterone	1	156.0×	0.016	CALR
positive regulation of cell cycle	1	147.8×	0.016	CALR
response to retinoic acid	1	127.7×	0.017	ASXL1
heart morphogenesis	1	124.8×	0.017	ASXL1
positive regulation of substrate adhesion-dependent cell spreading	1	124.8×	0.017	CALR
protein localization to nucleus	1	117.0×	0.017	CALR

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
U2AF1	1	2
CALR	0	0
ASXL1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	U2AF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
U2AF1	8	Binding:8
CALR	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	U2AF1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	U2AF1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CALR, ASXL1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CALR	1	—
ASXL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 290.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	102
PHASE1	67
Not specified	56
PHASE1/PHASE2	36
PHASE3	18
EARLY_PHASE1	7
PHASE4	2
PHASE2/PHASE3	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07498205	PHASE4	NOT_YET_RECRUITING	Comparing Momelotinib and Ruxolitinib in People With Untreated Myelofibrosis and Low Blood Cell Counts
NCT05447260	PHASE4	UNKNOWN	A New Prognostic Stratification-based Safety and Efficacy Study of Ruxolitinib in Myelofibrosis
NCT03480360	PHASE3	ACTIVE_NOT_RECRUITING	Haploidentical Allogeneic Peripheral Blood Transplantation: Examining Checkpoint Immune Regulators’ Expression
NCT04468984	PHASE3	ACTIVE_NOT_RECRUITING	Study of Oral Navitoclax Tablet in Combination With Oral Ruxolitinib Tablet Versus Best Available Therapy to Assess Change in Spleen Volume in Adult Participants With Relapsed/Refractory Myelofibrosis
NCT04562389	PHASE3	ACTIVE_NOT_RECRUITING	Study of Selinexor in Combination With Ruxolitinib in Myelofibrosis
NCT04576156	PHASE3	ACTIVE_NOT_RECRUITING	A Study Comparing Imetelstat Versus Best Available Therapy for the Treatment of Intermediate-2 or High-risk Myelofibrosis (MF) Who Have Not Responded to Janus Kinase (JAK)-Inhibitor Treatment
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)
NCT06479135	PHASE3	RECRUITING	Study of Navtemadlin add-on to Ruxolitinib in JAK Inhibitor-Naïve Patients With Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib
NCT07539779	PHASE2/PHASE3	NOT_YET_RECRUITING	Luspatercept in Preventing Poor Erythroid Engraftment for Hematological Malignancies With Moderate to Severe Myelofibrosis
NCT00235391	PHASE3	COMPLETED	Expanded Access of Deferasirox to Patients With Congenital Disorders of Red Blood Cells and Chronic Iron Overload
NCT00354120	PHASE2/PHASE3	COMPLETED	Thymoglobuline Versus Alemtuzumab in Patients Undergoing Allogeneic Transplant
NCT00438958	PHASE3	COMPLETED	Sibling Donor Peripheral Stem Cell Transplant or Sibling Donor Bone Marrow Transplant in Treating Patients With Hematologic Cancers or Other Diseases
NCT00934544	PHASE3	COMPLETED	Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II: The COMFORT-II Trial
NCT01493414	PHASE3	COMPLETED	INC424 for Patients With Primary Myelofibrosis, Post Polycythemia Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis.
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
NCT04472598	PHASE3	COMPLETED	Study of Oral Navitoclax Tablet In Combination With Oral Ruxolitinib Tablet When Compared With Oral Ruxolitinib Tablet To Assess Change In Spleen Volume In Adult Participants With Myelofibrosis
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)
NCT04617028	PHASE3	COMPLETED	Jaktinib Versus Hydroxycarbamide in Subjects With Intermediate-2 or High-risk Myelofibrosis
NCT00095784	PHASE2	ACTIVE_NOT_RECRUITING	Decitabine in Treating Patients With Myelofibrosis
NCT02506933	PHASE2	ACTIVE_NOT_RECRUITING	Multi-antigen CMV-MVA Triplex Vaccine in Reducing CMV Complications in Patients Previously Infected With CMV and Undergoing Donor Hematopoietic Cell Transplant
NCT03069326	PHASE2	ACTIVE_NOT_RECRUITING	A Clinical Study to Test the Effects of Ruxolitinib And Thalidomide Combination for Patients With Myelofibrosis
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
NCT03314974	PHASE2	RECRUITING	Myeloablative Allo HSCT With Related or Unrelated Donor for Heme Disorders
NCT03645824	PHASE2	ACTIVE_NOT_RECRUITING	Myelofibrosis Treated With Pacritinib Before aSCT. (HOVON134MF)
NCT04060277	PHASE2	ACTIVE_NOT_RECRUITING	Triplex Vaccine in Preventing CMV Infection in Patients Undergoing Hematopoietic Stem Cell Transplantation
NCT04176198	PHASE1/PHASE2	RECRUITING	A Study of Oral Nuvisertib (TP-3654) in Patients 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
NCT04562870	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate Single Agent Selinexor Versus Physician’s Choice in Participants With Previously Treated Myelofibrosis
NCT04640025	PHASE2	ACTIVE_NOT_RECRUITING	A Rollover Study to Provide Continued Treatment for Participants Previously Enrolled in Studies of Itacitinib
NCT04655118	PHASE2	RECRUITING	Study of TL-895 in Subjects With Myelofibrosis or Indolent Systemic Mastocytosis
NCT04679870	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral GB2064 in Participants With Myelofibrosis
NCT04817007	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Assess the Safety and Tolerability of BMS-986158 Alone and in Combination With Either Ruxolitinib or Fedratinib in Participants With Blood Cancer (Myelofibrosis)
NCT04888741	PHASE2	RECRUITING	Methods of T Cell Depletion Trial (MoTD)
NCT05031897	PHASE2	RECRUITING	Two Step Haplo With Radiation Conditioning

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RUXOLITINIB	4	67
METHOTREXATE	4	10
PACRITINIB	4	9
FEDRATINIB	4	8
MOMELOTINIB	4	5
POMALIDOMIDE	4	3
SELINEXOR	4	3
BASILIXIMAB	4	2
DASATINIB ANHYDROUS	4	2
DECITABINE	4	2
DEFERASIROX	4	2
LETERMOVIR	4	2
LUSPATERCEPT	4	2
ROPEGINTERFERON ALFA-2B	4	2
TAGRAXOFUSP	4	2
ALLOPURINOL	4	1
ARSENIC TRIOXIDE	4	1
AXATILIMAB	4	1
AZACITIDINE	4	1
CEDAZURIDINE	4	1
CRIZANLIZUMAB	4	1
DANAZOL	4	1
FLUDARABINE PHOSPHATE	4	1
FOSCARNET	4	1
FOSCARNET SODIUM	4	1
FOSTAMATINIB	4	1
FOSTAMATINIB DISODIUM	4	1
GANCICLOVIR	4	1
HYDROXYUREA	4	1
IDELALISIB	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 1 predictive associations from 1 curated evidence items; also 7 prognostic, 2 oncogenic.

Molecular subtype	Therapy	Effect	Level	CIViC
NTRK2 A203T	Entrectinib + Larotrectinib	Sensitivity/Response	CIViC D	EID8620