Recurrent Amplified Regions on the Long Arm of Chromosome 1 (1q) Are Associated with Disease Progression In Ph-Negative Myeloproliferative Neoplasms (MPN)

Abstract 3087

Trisomy of all or part of the long arm of chromosome 1 (1q) is a recurrent abnormality frequently observed at diagnosis in myeloproliferative neoplasms (MPN). Recently, we reported that jumping translocations involving duplications of chromosome 1q (1qJT) represent a clonal marker associated with high risk of transformation to acute myelogenous leukemia (AML) in both MPN and myelodysplastic syndrome (MDS). Breakpoints are often found at either 1q12 or 1q21 (Najfeld et al BJH 2010). Consequently, we hypothesized that these regions are likely to contain a gene or cluster of genes under selection for amplification associated with disease progression. To investigate this, we karyotyped 13 patients (7 males and 6 females) with MPN (primary myelofibrosis [MF]=7, essential thrombocythemia [ET]=2, ET->polycythemia vera- [PV]=1, ET or PV->MF=2, ET->MF->AML=1). Ten of these 13 patients (pts) had an abnormal karyotype, while 3 patients had a normal karyotype. Of pts with an abnormal karyotype, four had trisomy 1q and two had duplication 1q (q12 to q31). The breakpoint 1q12 was observed in 3 pts while the breakpoint 1q21 was identified in 4 pts. One pt had two different populations of cells with a 1q duplication (1q): 36% of cells had a 1q21 breakpoint while 6% cells had a 1q12 breakpoint as identified by FISH using 1q12 and 1q21 specific FISH probes. Additionally, one pt had trisomy for chromosomes 8 and 9, and one had a balanced t(1;9)(p36;p24.1) abnormality. JAK2V617F, an activating mutation implicated in MPN, was present in 6 pts. Of the 13 pts six progressed to AML or had an aggressive disease course that required stem cell transplantation. To map the boundaries of the minimally amplified regions on chromosome 1q associated with disease progression, DNA was isolated from the MPN cells of these 13 patients and genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. Copy number abnormalities were assessed by Genomic Segmentation (Partek Genomic Suite, St Louis, MO). This analysis revealed seven regions that were recurrently amplified (amplified in at least 4 MPN cases but not in normal controls). Of these regions, three were in 1q21.1 and the rest were telomeric to 1q21. We identified six patients with amplifications in 1q21.1, in contrast to the four identified by karyotype analysis. Of these, one pt had a normal karyotype and was JAK2V617F negative. Intriguingly, the region on 1q21 amplified in this patient was also amplified in the relapse sample of another patient at the time of progression to AML. Of note, this region includes PDE4DIP, which had previously shown to be part of a t(1;5)(q23;q33) translocation in MPN associated with eosinophilia. Of the other recurrent amplifications four pts had a gain of 1q32.1 which includes MDM4, a known regulator of the p53 tumor suppressor. Thus, these data suggest that fine mapping of recurrently amplified regions of chromosome 1q may reveal genes under pressure for amplification in high-risk MPN or that may be involved in the high-risk 1qJT found in both MPN and MDS.