Combination of myeloproliferative neoplasm driver gene activation with mutations of splice factor or epigenetic modifier genes increases risk of rapid blastic progression

Abstract

Objectives Myeloproliferative neoplasms (MPN) comprising polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) follow a bi‐phasic course of disease with fibrotic and/or blastic progression. At presentation in the chronic phase, currently there are only insufficient tools to predict the risk of progression in individual cases. Methods In this study, chronic phase MPN (16 PMF, 11 PV, and 11 MPN unclassified) with blastic transformation during course of disease (n = 38, median follow‐up 5.3 years) were analyzed by high‐throughput sequencing. MPN cases with a comparable follow‐up period and without evidence of blast increase served as control (n = 63, median follow‐up 5.8 years). Results Frequent ARCH/CHIP‐associated mutations (TET2, ASXL1, DNMT3A) found at presentation were not significantly associated with blastic transformation. By contrast, mutations of SRSF2, U2AF1, and IDH1/2 at first presentation were frequently observed in the progression cohort (13/38, 34.2%) and were completely missing in the control group without blast transformation during follow‐up (P = .0007 for SRSF2; P = .0063 for U2AF1 and IDH1/2). Conclusion Unlike frequent ARCH/CHIP alterations (TET2, ASXL1, DNMT3A), mutations in SRSF2, IDH1/2, and U2AF1 when manifest already at first presentation provide an independent risk factor for rapid blast transformation of MPN.

Molecular Progression of Myeloproliferative and Myelodysplastic/Myeloproliferative Neoplasms: A Study on Sequential Bone Marrow Biopsies

“…The prognostic impact of these mutations was particularly pronounced in MPN: in instances bearing such mutations, progressions occurred within a median of 1.5 years, while MPN cases lacking such mutations not only had lower frequency of transformation but also a median progression-free survival of over 10 years. Again, this partially reflects the insights already gained from other studies, as particularly ASXL1, SRSF2 and TP53 are known-among others-to be associated with a higher probability to develop AML in the background of MPN [5,9,42]. Other mutations described to be harbingers of adverse prognosis, such as IDH1/2 or RUNX1, did not correlate with AML transformation in our cohort, which is most probably due to our limited sample size [42,43].…”

“…Importantly, CHIP-associated mutations ( ASXL1 , DNMT3A , TET2 ) found at presentation do not seem to be significantly associated with transformation. By contrast, mutations of IDH1/2 , SRSF2 and/or U2AF1 at first presentation are linked to progression [ 9 ].…”

Rapid progression of myelofibrosis in polycythemia vera patient carrying SRSF2 c.284C>A p.(Pro95His) and unique ASXL1 splice site c.1720‐2A>G variant

“… 35 The above‐mentioned strategy may delay the disease evolution to fibrotic phase, which itself is now considered an independent risk factor for a rapid blast progression of MPN. 41 , 42 …”

Progression in Ph-Chromosome-Negative Myeloproliferative Neoplasms: An Overview on Pathologic Issues and Molecular Determinants

“…Unfavourable outcomes and a higher cumulative risk of BP occurrence in PMF patients with low risk were related to the presence vs. the absence of HRM ( ASXL1 , IDH1 /2, EZH2 , SRSF2 ) [ 87 , 88 , 89 ]. Nonetheless, the role of ASXL1 mutation as the sole mutation has recently been debated, with the suggestion that its poor prognostic role may only be effective if associated with mutations in TP53 or in other high-risk genes [ 90 , 91 ]. Additionally, something noteworthy is the observation by Bartels et al [ 90 ], where among those MPN that developed a BP, IDH1 / IDH2 hot-spot mutations mostly co-occurred with SRSF2 and U2AF1 mutations.…”

“…Nonetheless, the role of ASXL1 mutation as the sole mutation has recently been debated, with the suggestion that its poor prognostic role may only be effective if associated with mutations in TP53 or in other high-risk genes [ 90 , 91 ]. Additionally, something noteworthy is the observation by Bartels et al [ 90 ], where among those MPN that developed a BP, IDH1 / IDH2 hot-spot mutations mostly co-occurred with SRSF2 and U2AF1 mutations. Given that JAK2 /IDH-mutated mice do not develop overt leukemia [ 91 ], it is possible that IDH1 / IDH2 are not key-genes in leukemic transformation but rather SRSF2 is.…”