TY - CHAP
T1 - Mutational landscape of blast phase myeloproliferative neoplasms (MPN-BP) and antecedent MPN
AU - Pasca, Sergiu
AU - Chifotides, Helen T.
AU - Verstovsek, Srdan
AU - Bose, Prithviraj
N1 - Funding Information:
S.V. received research funding from Sierra Oncology, Incyte, Roche, NS Pharma, Celgene (now BMS), Gilead, Promedior, CTI BioPharma, AbbVie, Blueprint Medicines, Novartis, PharmaEssentia, Italfarmaco, Protagonist Therapeutics, Constellation Pharmaceuticals, and Kartos Therapeutics. P.B. reports honoraria from Incyte, Celgene (now BMS), CTI BioPharma, Kartos, Novartis, Sierra Oncology, and Blueprint Medicines Corporation; and research support from Incyte, Celgene (now BMS), CTI BioPharma, Kartos, Blueprint Medicines, Constellation, Astellas, Pfizer, NS Pharma, and Promedior.
Funding Information:
This work was supported, in part, by the MD Anderson Cancer Center Support Grant P30 CA016672 from the National Cancer Institute (National Institutes of Health).
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/1
Y1 - 2022/1
N2 - Myeloproliferative neoplasms (MPN) have an inherent tendency to evolve to the blast phase (BP), characterized by ≥ 20% myeloblasts in the blood or bone marrow. MPN-BP portends a dismal prognosis and currently, effective treatment modalities are scarce, except for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in selected patients, particularly those who achieve complete/partial remission. The mutational landscape of MPN-BP differs from de novo acute myeloid leukemia (AML) in several key aspects, such as significantly lower frequencies of FLT3 and DNMT3A mutations, and higher incidence of IDH1/2 and TP53 in MPN-BP. Herein, we comprehensively review the impact of the three signaling driver mutations (JAK2 V617F, CALR exon 9 indels, MPL W515K/L) that constitutively activate the JAK/STAT pathway, and of the other somatic non-driver mutations (epigenetic, mRNA splicing, transcriptional regulators, and mutations in signal transduction genes) that cooperatively or independently promote MPN progression and leukemic transformation. The MPN subtype, harboring two or more high-molecular risk (HMR) mutations (epigenetic regulators and mRNA splicing factors) and “triple-negative” PMF are among the critical factors that increase risk of leukemic transformation and shorten survival. Primary myelofibrosis (PMF) is the most aggressive MPN; and polycythemia vera (PV) and essential thrombocythemia (ET) are relatively indolent subtypes. In PV and ET, mutations in splicing factor genes are associated with progression to myelofibrosis (MF), and in ET, TP53 mutations predict risk for leukemic transformation. The advent of targeted next-generation sequencing and improved prognostic scoring systems for PMF inform decisions regarding allo-HSCT. The emergence of treatments targeting mutant enzymes (e.g., IDH1/2 inhibitors) or epigenetic pathways (BET and LSD1 inhibitors) along with new insights into the mechanisms of leukemogenesis will hopefully lead the way to superior management strategies and outcomes of MPN-BP patients.
AB - Myeloproliferative neoplasms (MPN) have an inherent tendency to evolve to the blast phase (BP), characterized by ≥ 20% myeloblasts in the blood or bone marrow. MPN-BP portends a dismal prognosis and currently, effective treatment modalities are scarce, except for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in selected patients, particularly those who achieve complete/partial remission. The mutational landscape of MPN-BP differs from de novo acute myeloid leukemia (AML) in several key aspects, such as significantly lower frequencies of FLT3 and DNMT3A mutations, and higher incidence of IDH1/2 and TP53 in MPN-BP. Herein, we comprehensively review the impact of the three signaling driver mutations (JAK2 V617F, CALR exon 9 indels, MPL W515K/L) that constitutively activate the JAK/STAT pathway, and of the other somatic non-driver mutations (epigenetic, mRNA splicing, transcriptional regulators, and mutations in signal transduction genes) that cooperatively or independently promote MPN progression and leukemic transformation. The MPN subtype, harboring two or more high-molecular risk (HMR) mutations (epigenetic regulators and mRNA splicing factors) and “triple-negative” PMF are among the critical factors that increase risk of leukemic transformation and shorten survival. Primary myelofibrosis (PMF) is the most aggressive MPN; and polycythemia vera (PV) and essential thrombocythemia (ET) are relatively indolent subtypes. In PV and ET, mutations in splicing factor genes are associated with progression to myelofibrosis (MF), and in ET, TP53 mutations predict risk for leukemic transformation. The advent of targeted next-generation sequencing and improved prognostic scoring systems for PMF inform decisions regarding allo-HSCT. The emergence of treatments targeting mutant enzymes (e.g., IDH1/2 inhibitors) or epigenetic pathways (BET and LSD1 inhibitors) along with new insights into the mechanisms of leukemogenesis will hopefully lead the way to superior management strategies and outcomes of MPN-BP patients.
KW - Clonal evolution
KW - Driver mutations
KW - Epigenetic regulators
KW - Essential thrombocythemia (ET)
KW - IDH1, IDH2
KW - JAK/STAT pathway
KW - JAK2 V617F
KW - Leukemic transformation
KW - MPN in accelerated phase (MPN-AP)
KW - MPN in blast phase (MPN-BP)
KW - Myelofibrosis (MF)
KW - Non-driver mutations
KW - Polycythemia vera (PV)
KW - Post-myeloproliferative neoplasm (MPN) acute myeloid leukemia (AML)
KW - RNA splicing factors
KW - TP53
KW - Transcriptional regulators
UR - http://www.scopus.com/inward/record.url?scp=85121672915&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85121672915&partnerID=8YFLogxK
U2 - 10.1016/bs.ircmb.2021.02.008
DO - 10.1016/bs.ircmb.2021.02.008
M3 - Chapter
C2 - 35153007
AN - SCOPUS:85121672915
SN - 9780323899413
T3 - International Review of Cell and Molecular Biology
SP - 83
EP - 124
BT - Cellular and Molecular Aspects of Myeloproliferative Neoplasms - Part B
A2 - Bartalucci, Niccolò
PB - Elsevier Inc.
ER -