Genetic Basis and Molecular Pathophysiology of Classical Myeloproliferative Neoplasms
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From www.bloodjournal.org by guest on March 16, 2017. For personal use only. Review Series MYELOPROLIFERATIVE NEOPLASMS Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms William Vainchenker1-3 and Robert Kralovics4 1Unit´eMixte de Recherche (UMR) 1170, INSERM, Villejuif, France; 2Gustave Roussy, Villejuif, France; 3Universit´e Paris-Saclay, UMR 1170, Villejuif, France; and 4Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria The genetic landscape of classical myelopro- vera, essential thrombocythemia (ET), and development of anemia or pancytopenia. liferative neoplasm (MPN) is in large part primary myelofibrosis (PMF) whereas CALR Both heterogeneity of classical MPNs and elucidated. The MPN-restricted driver muta- and MPL mutants are found in ET and PMF. prognosis are determined by a specific tions, including those in JAK2, calreticulin Other mutations in genes involved in epige- genomic landscape, that is, type of MPN (CALR), and myeloproliferative leukemia vi- netic regulation, splicing, and signaling co- driver mutations, association with other rus (MPL), abnormally activate the cytokine operate with the 3 MPN drivers and play a key mutations, and their order of acquisition. receptor/JAK2 pathway and their down- role in the PMF pathogenesis. Mutations in However, factors other than somatic mu- stream effectors, more particularly the STATs. epigenetic regulators TET2 and DNMT3A are tations play an important role in disease The most frequent mutation, JAK2V617F, involved in disease initiation and may pre- initiation as well as disease progression activates the 3 main myeloid cytokine recep- cede the acquisition of JAK2V617F. Other such as germ line predisposition, inflam- tors (erythropoietin receptor, granulocyte mutations in epigenetic regulators such as mation, and aging. Delineation of these colony-stimulating factor receptor, and MPL) EZH2 and ASXL1 also play a role in disease environmental factors will be important to whereas CALR or MPL mutants are re- initiation and disease progression. Muta- better understand the precise pathogene- stricted to MPL activation. This explains why tions in the splicing machinery are predom- sis of MPN. (Blood. 2017;129(6):667-679) JAK2V617F is associated with polycythemia inantly found in PMF and are implicated in the Introduction The classical myeloproliferative neoplasms (MPNs), also called BCR- subtypes can be observed, as documented by the progression of ET and 2 ABL MPNs, are the most frequent diseases among the myeloprolif- PV to secondary myelofibrosis (MF). Furthermore, boundaries between erative disorders. MPNs are characterized by excessive production of these 3 disorders cannot be well established, especially between ET and terminally differentiated blood cells that are fully functional. Classical PMF. Thus, transitional entities may emerge describing disease states MPNs have been classified into 3 entities: polycythemia vera (PV), such as prefibrotic PMF (or early PMF) that displays an ET phenotype at essential thrombocythemia (ET), and primary myelofibrosis (PMF), diagnosis with typical bone marrow histology, but with a high probability which have frequent disease-related complications, such as venous and of progression to MF and worse prognosis than true ET.3 arterial thrombosis, hemorrhages, and transformation to acute myeloid Somatic mutations are responsible for clonal expansion of HSCs not leukemia (AML).1 All MPN entities arise from a single somatically only in MPNs, but also in most types of myeloid malignancies. High- mutated hematopoietic stem cell (HSC) that clonally expands and gives resolution genome analysis using microarray and next-generation rise to virtually all myeloid cells, and B and natural killer (NK) cells. sequencing (NGS) resulted in the discovery of several gene mutations The clonal expansion of the MPN HSC is accompanied by single or across all myeloid malignancies. Only relatively few of these gene multilineage hyperplasia. PV is characterized not only by an excess mutations are found associated with a single or limited number of of erythrocytes and predominant erythroid lineage involvement, but disease entities. Therefore, we classify these mutations into those that is also associated with a variable hyperplasia of the megakaryocytic/ are “restricted to MPN” and those that are “nonrestricted” and are found granulocytic lineages. ET is characterized by an increased platelet count also in other myeloid malignancies (Table 1). with a megakaryocytic hyperplasia, whereas PMF is a more heteroge- neous disorder both by its clinical and biological characteristics, defined by the presence of bone marrow fibrosis (excess of collagen fibers) and megakaryocytic hyperplasia. Myeloproliferation in PMF initially predominates in the bone marrow and later expands to extramedullary Mutations restricted to MPNs and their role in sites, such as the spleen. Although the clinical presentations of the 3 MPN the MPN pathogenesis entities are different in their typical forms, establishment of precise JAK2 gene mutations diagnosis at disease onset is often challenging. This is reflected by the 2 2016 revision of the World Health Organization (WHO) diagnostic Before 2005, the molecular pathogenesis of the BCR-ABL1 classical criteria for MPN.2 In many cases, a continuum between these disease MPNs was unknown. In 2005, a major breakthrough was the discovery Submitted 15 October 2016; accepted 6 December 2016. Prepublished online © 2017 by The American Society of Hematology as Blood First Edition paper, 27 December 2016; DOI 10.1182/blood-2016-10- 695940. BLOOD, 9 FEBRUARY 2017 x VOLUME 129, NUMBER 6 667 From www.bloodjournal.org by guest on March 16, 2017. For personal use only. 668 VAINCHENKER and KRALOVICS BLOOD, 9 FEBRUARY 2017 x VOLUME 129, NUMBER 6 Table 1. Somatic mutations in MPN Gene function and symbol Location Type of mutations Protein function Frequency Consequences Reference Signaling MPN driver JAK2 9p24 JAK2V617F Tyrosine kinase associated with 95% PV, 50%-60% PMF and ET Increased RBC, platelet, and 4-7 cytokine receptors granulocyte production JAK2 exon 12 3% PV Increased RBC 17 MPL 1p34 MPL515L/K/A/R TPOR 2%-3% ET Increased platelet production 19, 22, 23 MPLS505N Other missense 3-5% PMF 25 mutations CALR 19p13 Indel exon 9 Mutant: activator of MPL 20%-25% ET, 25%-30% PMF Increased platelet production 28, 29 Other signaling LNK 12q24 Missense (loss of Negative regulator of JAK2 1% ET, 2% PMF Synergy with JAK2V617F- 35 function) deletion Disease progression CBL 11q23;3 Missense (loss of Cytokine receptor internalization 4% PMF Disease progression 110 function) (progression to AML) NRAS 1p13.2 Missense (activation) ERK/MAPK signaling Rare PMF Progression to leukemia (5%- 65 10% in secondary AML) NF1 17q11 Missense deletion ERK/MAPK signaling Rare PMF Progression to leukemia (5%- 66 10% in secondary AML) FLT3 13q12 FLT3-ITD Cytokine receptor (FLT3-L) MPN (,3%) Progression to leukemia (10%- 100 15% in secondary AML) DNA methylation TET2 4q24 Missense, nonsense a-Ketoglutarate–dependent 10%-20% MPN (ET, PV, and Initiation, 70 deletion dioxygenase PMF) Oxidation of 5mC into 5hmC and Mutations on 2 alleles active 5mC demethylation associated with progression DNMT3A 2p23 Missense, hotspot DNA methylase, de novo 5%-10% MPN (ET, PV, and Initiation 74 methylation PMF) IDH1 2q33.3 Missense, hotspot Neomorphic enzyme, generation 1%-3% PMF Initiation, Disease progression 111 of 2-hydroxyglutarate blocking a-ketoglutarate–dependent enzymes IDH2 15q26.1 Missense, hotspot Neomorphic enzyme, generation 1%-3% PMF Initiation, Disease progression 111 of 2-hydroxyglutarate blocking a-ketoglutarate–dependent enzymes Histone modifications EZH2 7q35-36 Missense, indel H3K27 methyltransferase, loss 5%-10% PMF Initiation 82, 83 of function Disease progression ASXL1 20q11 Nonsense/ indel Chromatin-binding protein 25% PMF Initiation 69 associated with PRC1 and 2 1%-3% ET/PV Rapid progression Transcription factors TP53 17p13.1 Missense/ indel Transcription factor regulating ,5% (20% of sAML) Progression to leukemia 98 cell cycle, DNA repair and (mutations on both alleles) apoptosis complex karyotype CUX1 7q22 Deletion 7p Transcription factor regulating ,3% Progression to leukemia 112 TP53 and ATM IKZF1 7p12.2 Deletion 7p, indel Master transcription factor in ,3% Progression to leukemia 112 lymphopoiesis ETV6 12p13 Missense/ indel Transcription factor of the ETs ,3% Progression to leukemia 112 family RUNX1 21q22.3 Nonsense/ missense/ Master transcription factor in ,3% (10% of sAML) Progression to leukemia 112 indel hematopoiesis RNA splicing SRSF2 17q25.1 Missense, hotspot Serine/arginine-rich pre- RNA ,2% ET 10%-15% PMF Initiation? Progression 94 splicing factor (association with IDH mutations) SF3B1 2q33.1 Missense RNA-splicing factor 3b subunit ,3% ET Phenotypic change (anemia) 113 1, part of U2 U2AF1 21q22.3 Missense U2 small nuclear RNA-splicing 10%-15% PMF Phenotypic change (anemia) 94 factor ATM, ataxia-telangiectasia mutated; RBC, red blood cell; sAML, secondary AML. From www.bloodjournal.org by guest on March 16, 2017. For personal use only. BLOOD, 9 FEBRUARY 2017 x VOLUME 129, NUMBER 6 SOMATIC MUTATIONS AND MPNs 669 Figure 1. Role of cytokine receptors in the oncogenic properties of JAK2V617F and CALR mutants. (A) JAK2V617F activates signaling through the 3 main homodimeric receptors EPOR, MPL, and G-CSFR, which are involved in erythro- cytosis, thrombocytosis, and neutrophilia, respec- tively. (B) The CALR