Jumping Translocations of the Long Arms of Chromosome 1 (1qJT) in Myeloproliferative Neoplasms (MPNs) and Myelodysplastic Syndromes (MDS) Are Associated with High Risk of Transformation to Acute Myelogenous Leukemia (AML).

Abstract 1567

Poster Board I-591

Jumping translocations (JT) are rare cytogenetic events where by a part of one chromosome is translocated to several recipient chromosomes creating multiple related clones within a single patient (pt). Over two-thirds of the already ∼70 reported cases with JTs had multiple myeloma (JR Sawyer et al, 2005). The most frequent donor chromosome involved in JT is the long arm of chromosome 1 (+1q). Although abnormalities of 1q are the 4^th most common recurrent rearrangements in both MPN and MDS, 1qJT have been rarely reported in these disorders. Their role in the pathogenesis of MPN and MDS remains unknown. We report a study of 23 pts with myeloid malignancies to determine the role of 1qJT in MPN and MDS. Patient characteristics are shown in Table 1. Of 512 MPN pts (PV=361, PMF=151) cytogenetically evaluated at our institution, we identified 3 pts (PV=2, PMF=1) at diagnosis with 1qJT (0.6% incidence). Additionally 4 of 169 (PV=96, PMF=69) pts with MPN acquired 1qJT during the serial follow up studies over a period of 11 years (the overall incidence was 1.3%, and 4.2% in pts with cytogenetically abnormal karyotypes).

Table 1

Characteristics of 23 pts with 1qJT at baseline and sequential studies

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*One patient had stem cell transplantation

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The median follow up time was 78 months (mos) and the average time to acquire 1qJT was 58 mos. usually only one or two cells with +1q were initially identified but over time the number of partner chromosomes increased. In 4 pts who acquired 1qJT, this genetic event occurred an average after 5 years while in 1 pt it occurred after 11 years. However, once 1qJT was acquired, 3 of 4 pts developed AML, within an average time of 8 months. The transformation to AML was associated with an increased 1q translocated copy number, suggesting that 1qJT may be a marker of disease progression. By contrast, the incidence of 1qJT at diagnosis of MDS was 0.04% (4 of 1,000). Each of 4 pts, who presented with 1qJTs, had up to three different related clonal populations, all characterized by +1q translocated to 3 different chromosomes. The presence of 1qJT at diagnosis was associated with transformation to AML (3 of 4 pts) after less than 4 mos. Additionally of the 300 pts who were sequentially studied for over a period of 34 mos, 12 pts acquired 1qJT within 27 months (the overall incidence 4%, or 8% among the cytogenetically abnormal). Once 1qJT was acquired, transformation to AML occurred after 8 months (range 0-32) in 10 of 12 pts (83%). This was accompanied with an increased number of JT partner chromosomes. Overall, trisomy 1q, was “jumping” to as many as 11 different chromosomes, creating 11 related clonal populations. All chromosomes except 2, 10 and 12, were recipients of 1qJT, with a greater frequency affecting acrocentric chromosomes (55%). More importantly, 81% of the breakpoints in recipient chromosomes were in the pericentromeric regions. This study represents the largest series of pts with MPN and MDS characterized by 1qJT. The presence of 1qJT at diagnosis or the subsequent acquisition of 1qJT was associated with transformation to AML in 86% of MPN cases and 83% of MDS cases after an average of 8 months. The prognosis of pts with 1qJT tends to be dependent on the translocated 1q copy number: the higher the number of “jumping” 1q being translocated to different partner chromosomes the shorter the time to transformation to AML. These data strongly indicate that 1qJT in MPN and MDS patients represents clonal chromosomal rearrangements associated with a high risk of imminent transformation to AML.