Mutational profiling in myelofibrosis: implications for management
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PROGRESS IN HEMATOLOGY Progress in elucidation of molecular pathophysiology and its application to therapeutic decisions of MPNs
Mutational profiling in myelofibrosis: implications for management Prithviraj Bose1 · Srdan Verstovsek1 Received: 3 September 2019 / Accepted: 27 September 2019 © Japanese Society of Hematology 2019
Abstract Mutational profiling, usually by targeted next-generation sequencing, is increasingly performed on patients with myeloproliferative neoplasm-associated myelofibrosis (MF), whether primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF). “Driver” mutations in JAK2, MPL and indels in CALR underlie the vast majority of cases of PMF and post-ET MF; the remainder (≈ 10%) lack identifiable driver mutations, but other clonal markers are usually detectable. Nearly all patients with post-PV MF carry activating JAK2 mutations. In both PMF and post-ET MF, type 1/-like CALR mutations confer a favorable prognosis. Since both type 1/-like and type 2/-like CALR mutations have essentially the same functional consequence, this is a subject of intense research. Additional, “non-driver” mutations, mostly affecting genes encoding epigenetic modifiers or spliceosome components, e.g., ASXL1, EZH2, TET2, DNMT3A, SRSF2 and U2AF1, are frequently found; some of these are associated with inferior survival and have been incorporated into prognostic models. Some mutations, e.g., IDH1/2, are relatively infrequent in chronic phase but are substantially more common in blast phase, and are now therapeutically targetable. While mutational information does not currently influence choice of drug therapy in chronic-phase MF, the presence of a “high molecular risk” genotype is now routinely taken into account for transplant decision-making. Keywords Mutations · Myelofibrosis · JAK–STAT · Epigenetic · Splicing
Introduction The discovery in 2005 of the activating V617F mutation in the tyrosine kinase Janus kinase 2 (JAK2), integral to downstream signaling upon cell surface receptor binding by a multitude of growth factors and cytokines, ushered in the molecular era in myeloproliferative neoplasm (MPN) research [1–4]. The discovery of activating mutations in MPL, the thrombopoietin receptor, in a small proportion of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) followed in 2006 [5, 6]. The molecular driver underlying most cases of JAK2/MPL-wild type (WT) classic MPN remained elusive until insertions and deletions in exon 9 of the endoplasmic reticulum (ER) chaperone * Srdan Verstovsek [email protected] 1
Department of Leukemia, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030, USA
calreticulin (CALR) that activate the JAK-signal transducer and activator of transcription (STAT) pathway were discovered in 2013 [7, 8]. Thus today, only 10–15% of cases of ET and PMF, the so-called “triple negative” cases, lack a clearly identified molecular driver, although non-canonical JAK2 and MPL mutations have been describe
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