Genomic aberrations of myeloproliferative and myelodysplastic/myeloproliferative neoplasms in chronic phase and during disease progression.

INTRODUCTION: Myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) may transform into secondary myelofibrosis (MF) or evolve into acute myeloid leukemia (AML). The genetic mechanisms underlying disease progression in MPN and MDS/MPN patients remain unclear. The purpose of this study was to investigate sequential genomic aberrations identified by single nucleotide polymorphism array (SNP-A)-based karyotyping that can detect cryptic aberrations or copy neutral loss of heterozygosity (CN-LOH) in the chronic phase and during disease progression of MPN and MDS/MPN patients.

METHODS: The study group included 13 MPN and four MDS/MPN patients (seven polycythemia vera (PV); four essential thrombocythemia (ET); two MPN-unclassifiable (MPN-U); one chronic myelomonocytic leukemia (CMML); one atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML); and two MDS/MPN-unclassifiable (MDS/MPN-U)). Among them, five patients (two PV, two MPN-U, and one MDS/MPN-U) progressed to MF and three patients (one CMML, one aCML, and one MDS/MPN-U) transformed to AML. The median follow-up period was 70 months (range, 7-152). Whole-genome SNP-A (SNP 6.0; Affymetrix, Santa Clara, CA, USA)-based karyotyping and JAK2 mutation analysis were performed according to the manufacturer's instructions.

RESULTS: SNP-A showed 19 kinds of genomic aberrations, including seven gains, eight deletions, and four CN-LOH. CN-LOH of 9p involving JAK2 was the most common aberration, followed by 5q deletion and 9p gain. The incidence of genomic changes identified by SNP was not different in patients with disease progression (75%), compared with those without disease progression (56%) (P = 0.4). However, when excluding 9p CN-LOH, the incidence of genomic changes was significantly higher in patients with disease progression than in patients without disease progression (63% and 0%, respectively, P = 0.01). Among eight patients with disease progression, two patients (two MPN-U) showed abnormal SNP-A results, whereas metaphase cytogenetics (MC) analysis showed normal results at diagnosis and during follow-up. In nine patients without disease progression, SNP-A did not show any genomic aberrations except for 9p CN-LOH. In three patients (one PV, one aCML, and one MDS/MPN-U), clonal evolutions were identified by both MC and SNP-A according to disease progression. One PV patient who progressed to MF at 45 months after diagnosis showed sequential genomic changes from 9p CN-LOH to 9p gain by SNP-A. Results of JAK2 mutation analysis were variable depending on the patient. Most of the patients with 9p CN-LOH or 9p gain showed more than 50% of the JAK2 mutant alleles. In one patient (MDS/MPN-U) evolving to AML, the number of JAK2 mutant alleles decreased according to disease progression.

CONCLUSION: This study suggests sequential genomic changes identified by SNP-A may be associated with disease progression.