TY - JOUR
T1 - Myelofibrosis
T2 - Genetic Characteristics and the Emerging Therapeutic Landscape
AU - Tefferi, Ayalew
AU - Gangat, Naseema
AU - Pardanani, Animesh
AU - Crispino, John D.
N1 - Publisher Copyright:
© 2021 The Authors.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Primary myelofibrosis (PMF) is one of three myeloproliferative neoplasms (MPN) that are morphologically and molecularly interrelated, the other two being polycythemia vera (PV) and essential thrombocythemia (ET). MPNs are characterized by JAK-STAT- activating JAK2, CALR, or MPL mutations that give rise to stem cell-derived clonal myeloproliferation, which is prone to leukemic and, in case of PV and ET, fibrotic transformation. Abnormal megakaryocyte proliferation is accompanied by bone marrow fibrosis and characterizes PMF, while the clinical phenotype is pathogenetically linked to ineffective hematopoiesis and aberrant cytokine expression. Among MPN-associated driver mutations, type 1-like CALR mutation has been associated with favorable prognosis in PMF, while ASXL1, SRSF2, U2AF1-Q157, EZH2, CBL, and K/NRAS mutations have been shown to be prognostically detrimental. Such information has enabled development of exclusively genetic (GIPSS) and clinically integrated (MIPSSv2) prognostic models that facilitate individualized treatment decisions. Allogeneic stem cell transplantation remains the only treatment modality in MFwith the potential to prolong survival, whereas drug therapy, including JAK2 inhibitors, is directed mostly at the inflammatory component of the disease and is therefore palliative in nature. Similarly, disease-modifying activity remains elusive for currently available investigational drugs, while their additional value in symptom management awaits controlled confirmation. There is a need for genetic characterization of clinical observations followed by in vitro and in vivo preclinical studies that will hopefully identify therapies that target the malignant clone in MF to improve patient outcomes.
AB - Primary myelofibrosis (PMF) is one of three myeloproliferative neoplasms (MPN) that are morphologically and molecularly interrelated, the other two being polycythemia vera (PV) and essential thrombocythemia (ET). MPNs are characterized by JAK-STAT- activating JAK2, CALR, or MPL mutations that give rise to stem cell-derived clonal myeloproliferation, which is prone to leukemic and, in case of PV and ET, fibrotic transformation. Abnormal megakaryocyte proliferation is accompanied by bone marrow fibrosis and characterizes PMF, while the clinical phenotype is pathogenetically linked to ineffective hematopoiesis and aberrant cytokine expression. Among MPN-associated driver mutations, type 1-like CALR mutation has been associated with favorable prognosis in PMF, while ASXL1, SRSF2, U2AF1-Q157, EZH2, CBL, and K/NRAS mutations have been shown to be prognostically detrimental. Such information has enabled development of exclusively genetic (GIPSS) and clinically integrated (MIPSSv2) prognostic models that facilitate individualized treatment decisions. Allogeneic stem cell transplantation remains the only treatment modality in MFwith the potential to prolong survival, whereas drug therapy, including JAK2 inhibitors, is directed mostly at the inflammatory component of the disease and is therefore palliative in nature. Similarly, disease-modifying activity remains elusive for currently available investigational drugs, while their additional value in symptom management awaits controlled confirmation. There is a need for genetic characterization of clinical observations followed by in vitro and in vivo preclinical studies that will hopefully identify therapies that target the malignant clone in MF to improve patient outcomes.
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U2 - 10.1158/0008-5472.CAN-21-2930
DO - 10.1158/0008-5472.CAN-21-2930
M3 - Review article
C2 - 34911786
AN - SCOPUS:85125724029
SN - 0008-5472
VL - 82
SP - 749
EP - 763
JO - Cancer research
JF - Cancer research
IS - 5
ER -