Blood cancers driven by an acquired mutation in blood stem cells, most often in JAK2 — the same gene where several of this page's eight inherited variants also sit, but as a completely different, inherited kind of change.
Myeloproliferative neoplasms (MPN) are blood cancers marked by the excessive production of mature myeloid cells. They are driven, clinically, by an acquired (somatic) mutation in JAK2, CALR or MPL that arises in blood stem cells during a person's life — not by anything inherited. But epidemiology shows MPN has one of the highest heritable components of any cancer, and this page holds 8 germline variants from two studies that go looking for that inherited part.
A 2015 study of 3,437 MPN cases and 10,083 controls, in three stages, deliberately looked at cases without the classic somatic JAK2(V617F) driver mutation, to separate inherited risk from the acquired mutation's own effect. It found two genome-wide-significant signals in that group: rs12339666, itself in JAK2 — the same gene as the somatic driver, but an inherited variant with its own separate association — and a second signal in MECOM not on this page. Two further signals reached significance only once JAK2(V617F)-positive cases were added back in, and one of them tracked more specifically with essential thrombocythemia than with polycythemia vera, evidence that inherited risk differs by MPN subtype, not just by overall disease risk.
A 2020 study raised the sample size by more than two orders of magnitude — 3,797 cases against 1,152,977 controls — and found 17 MPN risk loci in total, 7 of them newly reported. Its central finding is mechanistic: MPN risk variants are enriched in the parts of the genome that stay accessible (open chromatin) specifically in haematopoietic stem cells, and higher genetic MPN risk associates with longer telomere length in leukocytes. Together these point at a shared story — inherited MPN risk works through how haematopoietic stem cells renew themselves, not simply through faster blood-cell production after the fact. Functional experiments in the same paper confirmed two of the newly found genes, CHEK2 and GFI1B, actually alter stem-cell function in the lab, not just in a statistical association. This page holds 7 of its variants, including a second, independent JAK2 locus and a different MECOM locus from the one the 2015 study found.
Three of this page's eight variants sit at or near JAK2 or MECOM — genes also altered by the acquired mutations that actually drive MPN and get tested for in the clinic. That overlap is coincidental in the sense that matters clinically: the germline variants here are common, weak, inherited risk factors found by comparing thousands of people; the somatic JAK2(V617F), CALR and MPL mutations that define and drive MPN arise separately, during a person's life, in blood stem cells, and are what a hematologist actually orders a test for.
Positions joined since this page was written
What this is The text above discusses the variants this page was written around. Since then the catalogue has joined 2 more positions to it, by shared trait or shared paper. They are listed here by the paper each came from; the text does not describe them, and each variant page carries that study's own record.
Bao EL et al. 2020, Nature rs62329718 (TET2), rs62471615 (MKLN1) — PMID:33057200
2025-08-28 · Vanda Pharmaceuticals, official press release (FDA Orphan Drug Designation)
FDA grants orphan drug status to a JAK2 mRNA-targeting drug for polycythemia vera
Verified directly against Vanda Pharmaceuticals' own press release. On 28 Aug 2025 the FDA granted orphan drug designation -- not approval -- to VGT-1849B, an antisense oligonucleotide that selectively targets JAK2 mRNA itself to reduce JAK2 protein production, rather than inhibiting the JAK2 enzyme the way currently approved JAK inhibitors (ruxolitinib, fedratinib, pacritinib) do. The press release states more than 95% of polycythemia vera patients (a myeloproliferative neoplasm subtype) carry the acquired JAK2 V617F mutation this page's clinical-detail section already describes as the actual disease driver. Orphan drug designation is a regulatory incentive for rare-disease development, not evidence the drug works or is available -- it has not been shown effective or safe in humans yet.
MPN is diagnosed by blood counts, bone marrow examination, and testing for the acquired JAK2(V617F), CALR or MPL mutation — not by the inherited variants on this page. None of the 8 germline variants here are used by any guideline to diagnose MPN or select treatment.
The loci described above come from population-level genetic studies comparing thousands of people with MPN to controls. They explain part of why MPN clusters in families and point at haematopoietic stem cell biology as the underlying mechanism of inherited risk — they do not predict whether, or which, MPN subtype any one person will develop, and they are a different question entirely from the somatic mutation testing used in real diagnosis.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Myeloproliferative Neoplasms comes down to these specific, well-studied positions — not a diagnosis.
The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 10 of 10 linked studies with a resolved discovery ancestry.
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Myeloproliferative Neoplasms. MyGeneLog™. https://www.mygenelog.com/conditions/myeloproliferative-neoplasms
Blood cancers marked by the excessive production of mature myeloid cells, driven clinically by an acquired mutation in JAK2, CALR or MPL that arises in blood stem cells during a person's life.
Partly. MPN has one of the highest heritable components known for any cancer, and genetic studies have found 17 inherited risk loci to date -- but the disease itself is actually driven by a separate, acquired (somatic) mutation, not by these inherited variants.
Because both are real and distinct. JAK2(V617F), an acquired mutation in blood stem cells, is the actual clinical driver of most MPN and what a hematologist tests for. Separately, this page holds two inherited (germline) variants that also happen to sit in JAK2 and carry their own, much weaker, population-level risk association -- a different kind of change in the same gene.
No. MPN is diagnosed by blood counts, bone marrow examination, and testing for the acquired driver mutation. These are population-level findings from thousands of people, not a way to predict an individual case.
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