Molecular characterization of 1p36 chromosomal alterations in hematological malignancies

Duhoux, François [UCL]

(eng) The characterization of chromosomal alterations by cytogenetics in hematological malignancies is important for diagnostic, prognostic, predictive and therapeutic purposes as well as for the better understanding of the physiopathological mechanisms of oncogenesis. Chromosomal band 1p36 is a cytogenetic band of 28 megabases located at the telomeric end of the short arm of chromosome 1. This region is primarily known for its constitutional deletions, but acquired 1p36 alterations are also frequent in various solid tumors, especially neuroblastomas, and in hematological malignancies, where they are known to be heterogeneous and are suspected to be related with tumoral progression. Instead of focusing on individual, already described, genetic alterations, or on a specific type of disease, we chose to study the 1p36 region as a whole, with the aim of identifying the genes involved in the different chromosomal alterations and the partner genes in chromosomal translocations, mapping the minimal deleted region(s) and trying to correlate our findings with the type of hematological malignancies and other available clinical data. We performed fluorescence in situ hybridization to characterize 120 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations. We showed that they can be subdivided into 3 subgroups: balanced translocations, telomeric rearrangements, and unbalanced rearrangements. Taken together, out of the 120 patients of our study, there were 66 patients with balanced translocations (55 myeloid, 11 lymphoid cases), 15 patients with telomeric rearrangements (11 myeloid and 4 lymphoid cases) and 39 patients with unbalanced, non-telomeric rearrangements (9 myeloid, 29 lymphoid and 1 undifferentiated case), the latter frequently associated with a highly complex karyotype. There was thus a predominance of balanced translocations in the myeloid subgroup and of unbalanced rearrangements in the lymphoid subgroup. In 39/66 cases with balanced translocations, the involved locus on 1p36 was the PRDM16 locus. PRDM16 is known to be rearranged in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with t(1;3)(p36;q21), sharing characteristics with AML and MDS with EVI1 (3q26.2) translocations. In our series, PRDM16 was rearranged with the RPN1 (3q21) locus in 30 cases and with other loci in 9 cases. The diagnosis was AML or MDS in most cases, except for 2 cases of lymphoid proliferation. We identified novel translocation partners of PRDM16, including transcription factors ETV6 and IKZF1. Translocations involving PRDM16 lead to its overexpression irrespective of the consequence of the rearrangement (fusion gene or promoter swap). Survival data suggest that patients with AML / MDS and PRDM16 translocations have a poor prognosis. There is an over-representation of therapy-related myeloid malignancies. If these results are confirmed, we suggest the addition of a “PRDM16”-entity in the World Health Organization classification of AML, related to the "EVI1"-entity. Apart from the cases where PRDM16 was rearranged, we showed that the breakpoints on 1p36 are more widely distributed than previously reported. We defined breakpoint cluster regions such as the TP73 locus. We precised the terminal 1p36 deletions in B-cell lymphomas [follicular lymphomas and diffuse large B-cell lymphomas with t(14;18)(q32;q21) as well as follicular lymphomas without t(14;18)], which has been suggested to have an adverse prognostic impact. We found novel partner regions on 1p36 for the known multi-partner genes HMGA2 and RUNX1. We also showed the presence of intra-chromosomal telomeric repetitive sequences in certain cases. We speculate that 1p36 rearrangements may be causal in the cases of balanced translocations (where they are often isolated, especially in myeloid disorders), while they may reflect the evolution of the hematological malignancy in the cases of unbalanced rearrangements (often found in complex karyotypes) and a genomic instability in the cases of telomeric rearrangements. Finally, we propose novel therapeutic options targeted on the genetic defect identified in certain cases of 1p36 alterations that we characterized. Innovative approaches, like next-generation sequencing, will certainly further refine our understanding of 1p36 rearrangements and unravel novel therapeutic targets.