Leukemic blasts in transformed JAK2-V617F–positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation.

Abstract

To study the role of the JAK2-V617F mutation in leukemic transformation, we examined 27 patients with myeloproliferative disorders (MPDs) who transformed to acute myeloid leukemia (AML). At MPD diagnosis, JAK2-V617F was detectable in 17 of 27 patients. Surprisingly, only 5 of 17 patients developed JAK2-V617F-positive AML, whereas 9 of 17 patients transformed to JAK2-V617F-negative AML. Microsatellite analysis in a female patient showed that mitotic recombination was not responsible for the transition from JAK2-V617F-positive MPD to JAK2-V617F-negative AML, and clonality determined by the MPP1 polymorphism demonstrated that the granulocytes and leukemic blasts inactivated the same parental X chromosome. In a second patient positive for JAK2-V617F at transformation, but with JAK2-V617F-negative leukemic blasts, we found del(11q) in all cells examined, suggesting a common clonal origin of MPD and AML. We conclude that JAK2-V617F-positive MPD frequently yields JAK2-V617F-negative AML, and transformation of a common JAK2-V617F-negative ancestor represents a possible mechanism. (Blood.

JAK2-negative ET patients do not display constitutively active JAK/STAT signaling

“…While several recent observations in patients with polycythemia vera suggest that the JAK2 V617F mutation is neither the sole nor the initial change leading to the development of this myeloproliferative disorder, its discovery nonetheless poses a significant increase in our understanding of molecular disease etiology [29][30][31][32][33]. For those remaining 8 -10% of PV patients, as well as for the 50 % of ET patients, who do not carry the JAK2 V617F mutation, however, the molecular cause of disease evolutions remains unclear.…”

Emergence of JAK2-mutant primary myelofibrosis in myelodysplastic syndrome: rare case report, literature review, and implications for clonal progression

“…Consistent with the existence of at least two serially distinct but related clones, both disorders were characterized by loss of the Y chromosome, yet RA was marked by 9% RS and del(20q), and PMF showed neither. Arguing for a third clonogenic intermediary, blastic progression of PMF ultimately resulted with loss of JAK2 V617F allele, as has been reported during the transformation of BCR-ABL1-negative MPNs [18,19].…”

Kinase drug discovery approaches in chronic myeloproliferative disorders

“…MF is a severe complication of these disorders and can either develop de novo without prior history of either PV or ET as in PMF or develop from the pathogenesis of ET or PV (Tefferi, 2000). Another pathological feature that is shared by all Ph(À) MPDs is the progression to leukemic transformation following long-term treatment with cytoreductive therapies (Cervantes et al, 1991;Theocharides et al, 2007). Although the disease progression can be slowed and certain symptoms alleviated were current treatments, therapies are not curative and collectively, these symptoms are associated with severe quality-of-life complications and morbidity.…”

“…In addition, there is evidence for an inherited germline allele that precedes and predisposes patients to acquire JAK2-V617F (Goerttler et al, 2005;Levine et al, 2006) as well as loss of chromosomal region 20q in some MPD patients. Although MPD conversion to AML is observed clinically at moderate levels and activating JAK chromosomal translocations are observed in leukemia, epidemiological data suggest that it is questionable that JAK2-V617F is a genetic driver in this context, suggesting that additional genetic alterations are required for full leukemic transformation (Theocharides et al, 2007). These observations notwithstanding, JAK2 inhibition with small-molecule inhibitors is sufficient to modulate disease progression pre-clinically in animal models, suggesting that JAK2 activation is sufficient for maintaining MPD (Pardanani et al, 2007).…”