Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms

Abstract

Patients with myeloproliferative neoplasms (MPNs) are at significant, cumulative risk of leukemic transformation to acute myeloid leukemia (AML), which is associated with adverse clinical outcome and resistance to standard AML therapies. We performed genomic profiling of post-MPN AML samples; these studies demonstrate somatic tumor protein 53 (TP53) mutations are common in JAK2V617F-mutant, post-MPN AML but not in chronic-phase MPN and lead to clonal dominance of JAK2V617F/TP53-mutant leukemic cells. Consistent with these data, expression of JAK2V617F combined with Tp53 loss led to fully penetrant AML in vivo. JAK2V617F-mutant, Tp53-deficient AML was characterized by an expanded megakaryocyte erythroid progenitor population that was able to propagate the disease in secondary recipients. In vitro studies revealed that post-MPN AML cells were sensitive to decitabine, the JAK1/2 inhibitor ruxolitinib, or the heat shock protein 90 inhibitor 8-Treatment with ruxolitinib or PU-H71 improved survival of mice engrafted with JAK2V617F-mutant, Tp53-deficient AML, demonstrating therapeutic efficacy for these targeted therapies and providing a rationale for testing these therapies in post-MPN AML. (1). Mutations in JAK2 have been identified in the majority of patients with PV, ET, and PMF (2-6), underscoring the importance of activated JAK-STAT signaling to the pathogenesis of chronicphase MPN. Despite the increasing use of empiric and targeted therapies, a subset of MPN patients transform to secondary acute myeloid leukemia (AML). Leukemic transformation occurs in 1%, 4%, and 20% of patients over a 10-y period in ET, PV, and PMF, respectively (7). MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo (8). Advanced age (>60 y) and exposure to chemotherapy increase the risk of leukemic transformation; however, the mechanisms and pathways that contribute to transformation from MPN to AML have not been well delineated. Importantly, the use of standard AML therapies, including induction chemotherapy, has not been shown to improve outcome for patients with post-MPN AML (8, 9). These data indicate a need for new models and improved therapeutic approaches to improve outcomes for patients who have transformed from MPN to AML and to identify genetic lesions associated with leukemic transformation.Genetic studies of paired samples before and after leukemic transformation have suggested there are at least two distinct routes for leukemic transformation. Some patients who present with a JAK2/MPL-positive MPN progress to JAK2/MPL-positive AML that is associated with the acquisition of additional genetic alterations (10-13). A second, more complex route to AML from MPN has been described in which a JAK2/MPL-positive MPN is followed by JAK2/MPL-negative AML (14, 15). Clonality studies using X-chromosome inactivation in informative females demonstrated that JAK2/MPL-positive MPN and JAK2/MPL-negative AML are clonally related, consistent with transformation of an antecedent, preJAK2...

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

“…The pathogenetic role of these other mutations is incompletely understood and might include cooperation with the driver mutations in facilitating disease progression [49,50]. Specific genes affected in this regard include those relevant to epigenetic (e.g., ASXL1, TET2, EZH2, IDH1, IDH2, DNMT3A), RNA splicing (e.g., SRSF2, U2AF1, SF3B1) or transcriptional (TP53, IKZF1, NF-E2, CUX1) regulation.…”

“…Mutations other than JAK2, CALR or MPL, which have been shown to have prognostic relevance in PMF, include ASXL1, SRSF2, EZH2, IDH1/2, and U2AF1 [51,52]. In addition, TP53, IDH2, SRSF2, and SH2B3 mutations have been reported to be over-represented in blastphase MPN, suggesting their relevance in disease progression [48,50,53]. Most noteworthy in this regard is TP53 loss, which is believed to make JAK2-mutated patients vulnerable to leukemic transformation [48,50].…”

Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations

“…[19][20][21] The prognosis of MPN patients has been found to be dependent on the presence and the number of some of these additional mutations, such as ASXL1, SRSF2, IDH1, or IDH2, 22,23 whereas TP53 mutations are highly correlated to the development of acute transformation. 21,24,25 Interestingly, particular combinations of mutations could better define subgroups of patients with different outcomes. 26 Such molecular complexity could also affect the response to treatment.…”

P53 deletion and NrasG12D cooperate for AML

“…8 A parallel could also be made with the overexpression of Jak2V617F in p53 2/2 mice, which induces leukemia. 9 Zhang et al observed a major increase in MPPs and MPs in Nras G12D p53 2/2 compared with controls. Importantly, these MPs displayed higher replating efficacy, and the transplantation of 10 000 MPs led exclusively to AML (as opposed to MPPs that led to both AML and T-ALL) in half of the animals, suggesting that they contain the LIC.…”

“…8,9 Although orbital radiation is usually welltolerated, long-term complications, such as premature cataract and dryness, are dosedependent-and exceeding 36 Gy may increase risks of ischemic retinopathy, optic atrophy, corneal ulceration, and neovascular glaucoma. RT of orbital MZL rarely needs to exceed 30 Gy, and I hope that the readers of the University of Miami study will not conclude that the higher the orbital RT dose, the better.…”