Science & Medicine

A myeloproliferative neoplasm….why me?

This is a shorter version of a more comprehensive article on familial MPDs that appears on the MPN Foundation website
Used with permission of The MPN Foundation.

By Zhenya Senyak

The odds are so high it’s almost a certainty. As a patient, the first time you heard the term myeloproliferative disorder it came out of the mouth of your doctor telling you that you had it.

For the patient, the concept of a haywire blood production system and the terminology are strange enough, but the novelty is almost total. Chances are no one in the patient’s family has ever heard of it either. The numbers just popped up on a routine blood test, out of the blue. Soaring platelets. Or high hematocrit. Something like that. A few tests, a visit to the hematologist and suddenly the patient is a member of a very exclusive medical club. It just seems so sporadic.

Given the circumstances it’s reasonable to wonder how it happened.

Is this MPD something you can catch like a bug, or does it come from diet or chemicals or drugs you did in high school? Obviously, it can’t be inherited since no one in the family has it. (Actually that’s only true about 93% of the time since an estimated 7 % of patients newly diagnosed with an MPD have a first degree relative with the same or another MPD.)

Sorting out familial MPDs is the subject of intensive worldwide MPD research. The idea that MPDs can be transmitted via the germline, the reproductive system, carrying the preprinted code in the DNA — like a bar code that will be scanned down the line to deliver a disease — opens invaluable lines of investigation

Ever since completion of the human genome project, complete human genome prototypes have been used to isolate oncogenic mutations. By comparing a healthy genome with a patients whose genome expresses a myeloproliferative diisorder the mutated, causative gene theoretically might be identified and replaced or neutralized.

That’s one reason to get excited about the research being done on Familial MPDs. Whether MPD patients inherited the mutation that has affected the orders issued by their hematopoietic stem cells or stumbled in a bad patch of radiation that zapped their marrow or something completely different, finding the cause of MPDs is the beginning of finding the cure.

And that’s exactly what happened with another MPD, chronic myeloid leukemia (CML). In 1960. Peter Nowell and David Hungerford discovered the Philadelphia Chromosome, a chromosomal abnormality found in CML patients, It would take another 13 years and the development of new staining and chromosome banding techniques before Janet Rowley would conclude that the Philadelphia chromosome was the result of a reciprocal translocation between chromosomes 9 and 22, thus setting the stage for its later description as an oncogenic BCR–ABL mutation. Discovering the cause led to the cure.

In 1996 Brian Druker discovered imatinib, a compound that binds to a receptor site in the BCR-ABL tyrosine kinase effectively shutting it down. This was the silver bullet that changed CML, one of the most dreaded blood diseases, from a death sentence to a manageable chronic illness.

So far, however, these discoveries did not establish a family connection. The genetic mutations known to cause an MPD were considered somatic, acquired chromosomal events that were not transmitted via the germline to succeeding generations.

After five labs independently discovered the JAK2 mutation in 2005, it appeared there was reason to hope a key factor in the development of MPDs had been uncovered. Virtually all patients with PV and about half with ET and MF have the JAK2 mutation.

By 2009, enthusiasm dampened a bit. The JAK2v617F. inhibitors did not clearly affect the clone itself or the progression of the MPD. They were effective in reducing the burden of the mutated JAK2 allele, alleviating such symptoms as splenomegaly, pruritis and night sweats. The jury is still out on some JAK2 inhibitors as the data accumulates but few expect these inhibitors, alone, to be the magic bullet.

The predominant thinking now among MPD researchers is that the JAK2 mutation is not inherited but it is possible a predisposition to develop the mutation can be transmitted through the germline.

The Harvard familial MPD study – In search of the source.
MPD Foundation grantees, Dr. Ben Ebert, of the Broad Institute and Dr. Ann Mullally of Harvard Medical School are part of the group studying the causes of familial MPDs from a different angle. . They are trying to determine the inherited genetic basis for the disease using carefully defined sequences of DNA to select promising candidates for full genomic sequencing. To improve the odds of success they’ve recruited a cohort of Ashkenazi Jews with familial MPD. (European, or Ashkenazi, Jews are diagnosed with MPDs at a higher rate than the general population.)

Researchers believe this might be another instance of the Founder Effect. Well-defined population groups living in relative isolation over long periods of time share more common genes and phenotypes. It’s possible an inherited gene, perhaps common to a mutation in a single ancestor, the Founder, might be triggering the MPD.

Dr. Ann Mullally believes it is “possible we’ll find something new about the biological development of MPDs because we’re taking an unbiased genomic approach to this research. We have no candidate gene. We couldn’t possibly sequence the whole genome of everyone in the cohort but we could do more detailed sequencing of a likely subset of the group. We believe there may well be overlap between what’s inherited and predisposed and what’s acquired that causes the MPD.”


*There is a more comprehensive informational White Paper published by the MPD Foundation, Nature or Nurture – the sources of our MPNs. available on-line as a PDF at

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