6. Polycythemia Vera, Essential Thrombocythemia and Primary Myelofibrosis
Polycythemia (Rubra) vera (PV) is a clonal hematopoietic neoplasm characterized by increased red cell mass and JAK2 V617F mutation in 95% cases, and potential to progress to myelofibrosis or transformation to acute myeloid leukemia. Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm affecting the megakaryocytic lineage and characterized by abnormally large megakaryocytes in the marrow and persistent thrombocytosis. Primary myelofibrosis (PMF) is characterized by megakaryocytic and myeloid proliferation and progressive fibrosis in the marrow. JAK2 V617F mutation is identified in approximately 40%–50% cases of ET and approximately 50% of PMF. Of note, JAK2 V617F mutation can be detected in healthy individuals by high sensitivity methods. CNAs were rare in PV and ET and approximately one third cases of PMF showed small genomic losses (<5 Mb) with 250K SNP array [68]. In terms of copy-neutral aberrations (UPD), recurrent changes were only observed on chromosome 9p. Rice et al. [69] confirmed that chromosome 9 abnormalities including 9p LOH, trisomy 9, amplifications of 9p13.3–23.3, 9q33.1–34.13, and 9q34.13 were most frequent in myeloproliferative neoplasms when analyzing 87 myeloproliferative neoplasmas (MPN) cases with an Affymetrix 250K SNP array. Other less frequent recurrent genetic alterations included gains of 1p36.31–36.33, 17q21.2–q21.31, and 17q25.1–25.3, and deletions affecting 18p11.31–11.32. In the study of genetic profiles of myeloproliferative neoplasms by 50K SNP array, Kawamata et al. [70] found rare genomic abnormalities in ET, and deletion of chromosomal regions harboring RB (13q14) or NF1 (17q11) in 25% PMF cases. aUPD involving JAK2 was found in five PV cases with homozygous JAK2 V617F [70]. A subpopulation with 9p aUPD was detected in 30% of PV and approximately 50% PMF cases, and UPD at 1p was identified in one case of PV. The relationship between JAK2 V617F mutation and 9p aUPD in PV was further addressed by Wang et al. [71]. They investigated 31 PV patients with SNP array and whole genome sequencing and validated the findings in 59 additional PV patients [71]. They defined four PV subgroups based on the quantitative relationship between JAK2 V617F and 9p aUPD: 42% of patients with heterozygous JAK2 V617F and no detectable 9p aUPD (subgroup I); 45% of patients with homozygous JAK2 V617F and an allelic fraction directly proportional to the level of 9p aUPD (subgroup II); 10% with 9p aUPD at approximately twice the level of heterozygous JAK2 V617F allelic burden (subgroup III) and 3% with trisomy 9p and two copies of JAK2 V617F allele (subgroup IV), which likely suggest different pathways leading to PV phenotype. These genomic profiling studies indicated that ET and PV are genomically stable and JAK2 on chromosome 9p is critical for the pathogenesis of MPN. A genome-wide associate study seems to support this, with the identification of a SNP in the JAK2 locus (rs10974944), which predisposed to the development of JAK2 V617F-positive myeloproliferative neoplasm [72].
A subset of the patients with MPNs eventually progresses to acute myeloid leukemia. Identification of acquired genetic alterations facilitating this transformation would be valuable for patient stratification. In a study comparing genome profiles of 88 cases of MPN and 71 cases of MPN-blasts phase with 50 and 250 K SNP arrays, leukemic transformation of MPN was accompanied by up to three-fold more genomic alterations per case than chronic phase [73]. The genomic regions commonly affected during leukemic transformation harbored established genes such as ETV6, TP53, and RUNX1, and also new candidate genes on 7q, 16q, 19p, and 21q. Trisomy 8 or amplification of 8q24 (MYC) was identified exclusively in JAK2 V617F(−) MPN-blast phase. A poor prognosis after leukemic transformation was associated with copy number-neutral loss of heterozygosity (CNN-LOH) on either 7q or 9p including homozygous JAK2 V617F. With higher resolution SNP 6.0 arrays, Rumi et al. [74] showed a close relationship between UPD and/or gain of chromosome 9p with progression from PV to post-PV myelofibosis, and genetic aberrations of chromosome 5, 7, or 17p associated with progression to AML and overall survival.