Novel evidence of a role for chromosome I pericentric heterochromatin in the pathogenesis of B-cell lymphoma and multiple myeloma

1q rearrangement is a remarkably frequent secondary chromosomal change in. both non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM), where it is as sociated with tumor progression. To gain insight into 1q rearrangement-asso ciated disease mechanisms, we used fluorescence in situ hybridization (FISH ) to search for recurring 1q breaks in 35 lymphoma samples (31 NHL patients and 4 lymphoma-derived cell lines) as well as 22 MM patients with cytogene tically determined 1q abnormalities. Strikingly, dual-color FISH analysis w ith chromosome 1 centromere and 1q12-specific probes identified constitutiv e heterochromatin band 1q12 as the single most frequent breakpoint site in both NHL and MM (39% and 89% of I q breaks, respectively). These rearrangem ents consistently generated aberrant heterochromatin/euchromatin junctions and gain of 1q12 material. A further 30% of NHL 1q breaks specifically invo lved two other novel, closely spaced sites (clusters I and II) within a 2.5 Mb region of proximal 1q21 (D1S36210 to D1S3623). A possible association b etween these sites and NHL subtype was evident; the cluster 1 rearrangement was frequent in follicular and diffuse large cell lymphoma, whereas the cl uster II rearrangement was more frequently observed in diffuse small-cell l ymphoma (2/2 marginal zone lymphomas, 1/2 atypical chronic lymphocytic leuk emias, and 1 lymphoplasmacytic lymphoma in this series). Candidate oncogene s bordering this interval (BCL9 and AFIQ) were not rearranged in any patien t except one (AFIQ). This study provides the first evidence of involvement of 1q12 constitutive heterochromatin in the pathogenesis of NHL and MM and indicates proximal 1q21 to be of specific pathological significance in NHL. (C) 2001, Wiley-Liss, Inc.