Targeted next-generation sequencing in blast phase myeloproliferative neoplasms

Abstract

Among 248 consecutive patients with blast phase myeloproliferative neoplasm (MPN-BP), DNA collected at the time of blast transformation was available in 75 patients (median age, 66 years; 64% men). MPN-BP followed primary myelofibrosis in 39 patients, essential thrombocythemia in 20 patients, and polycythemia vera in 16 patients. A myeloid neoplasm-relevant 33-gene panel was used for next-generation sequencing. Driver mutation distribution was 57%, 20%, 9%, and triple-negative 13%. Sixty-four patients (85%) harbored other mutations/variants, including 37% with ≥3 mutations; most frequent were 47%, 19%, 17%, 16%, 15%, and 13%; relative mutual exclusivity was expressed by, ,, ,, and mutations. Paired chronic-blast phase sample analysis was possible in 19 patients and revealed more frequent blast phase acquisition of, ,, ,, and mutations/variants. In multivariable analysis, and mutations/variants were associated with shorter survival duration; respective hazard ratios (HRs) (95% confidence interval [CI]) were 2.1 (95% CI, 1.1-3.8) and 3.0 (95% CI, 1.1-6.6). An all-inclusive multivariable analysis confirmed the prognostic relevance of mutations (HR, 1.9; 95% CI, 1.5-5.5) and also showed additional contribution from a treatment strategy that includes transplant or induction of complete or near-complete remission (HR, 0.3; 95% CI, 0.2-0.5). The current study points to specific mutations that might bear pathogenetic relevance for leukemic transformation in MPN and also suggest an adverse survival effect of mutations.

Myelofibrosis biology and contemporary management

“…99 Additionally, RUNX1 mutations predicted inferior survival in blast phase disease regardless of treatment strategy. 74 In a subsequent report, which interrogated risk factors for BT in 1,306 patients with chronic phase PMF, IDH1, SRSF2, or ASXL1 mutations; circulating blasts ≥ 3%; age >70 years and anaemia were identified as independent predictors of leukaemia-free survival. 100 This led to formulation of a predictive 3-tiered risk model for BT: high-risk (incidence 57%), intermediate-risk (incidence 17%) and low-risk (incidence 8%), which was superior in accuracy to MIPSS 70-plus version 2.0 and GIPSS.…”

“…73 Importantly, in regards to the impact of epigenetic aberrations on disease progression, a targeted next generation sequencing study performed on paired samples from chronic and blast phase MF noted frequent acquisition of ASXL1, EZH2, LNK, TET2, TP53 and PTPN11 mutations at blast phase. 74 Several studies have highlighted aberrant miRNA expression in MF, with specific miRNA signatures that distinguish MF granulocytes from those of healthy individuals. [75][76][77] In addition, miRNA-gene expression analyses provided insights into their potential contributions towards megakaryocytic hyperplasia.…”

Primary myelofibrosis: 2019 update on diagnosis, risk‐stratification and management

“…These mutations are mostly shared by patients with PV or ET . It is generally believed that driver mutations are essential for the MPN phenotype whereas the “other” mutations might contribute to disease progression and leukemic transformation …”

Deregulated Polycomb functions in myeloproliferative neoplasms

“…Among non-canonical PRC1 genes, loss-of-function mutations in BCOR occur in various hematological malignancies, such as AML, MDS, CMML, and lymphoid tumors ( Table 1), indicating that BCOR functions as a tumor suppressor in these tumors [70][71][72] Mice deficient for Bcor exon 4 (Bcor ∆E4/y ), which generate a truncated protein that cannot bind Bcl6, develop Notch-dependent T-ALL [73]. Mice lacking Bcor exon 9 and exon 10 (Bcor ∆E9−10/y ), which cannot bind Pcgf1, develop T-ALL at a similar latency to that of Bcor ∆E4/y mice and have myeloid-biased hematopoiesis.…”