Models of biclonal disease and the accumulation of genetic damage in the myeloproliferative neoplasms (MPN). (A) Models to explain the presence of biclonal disease in MPN patients, with two clones representing (i) the phylogenetically related progeny of a shared founder clone or (ii) independent clones arising from distinct stem cells. Direct evidence exists for both of these models in patients with chronic phase disease.23,24 (B) Mechanisms of disease progression in the JAK2 V617F–positive myeloproliferative neoplasms. In the presence of normal JAK2 signaling, DNA damage causes a modification (deamidation) in the pro-survival Bcl-XL protein, resulting in release of pro-apoptotic BH3-only proteins and subsequent cell death by apoptosis. Expression of mutant JAK2 not only increases DNA damage but also inhibits the normal Bcl-XL deamidation response; the net result is survival of the MPN clone despite the accumulation of genetic damage. HSC indicates hematopoietic stem cell; dBcl-XL: deamidated Bcl-XL.
