Common-variable immunodeficiency-related lymphomas associate with mutations and rearrangements of BCL-6: pathogenetic and histogenetic implications

Common-variable immunodeficiency (CVI) patients develop non-Hodgkin's lymphomas (NHL), mainly B-lineage diffuse large-cell lymphomas (DLCL), with a high relative risk. The molecular pathogenesis of CVI-related NHL (CVI-NHL) is unknown. Here we aimed at providing a detailed molecular characterization of CVI-NHL. Rearrangements of BCL-6 were detected in two thirds of CVI-NHL cases examined. All 3 CVI-NHL also harbored point mutations of the BCL-6 5' noncoding regions, which constitute a marker of B-cell transit through the germinal center (GC). The number and molecular pattern of BCL-6 mutations in CVI-NHL were similar to that detected in DLCL of immunocompetent hosts and in DLCL arising in other immunodeficiency settings. Microsatellite instability occurred in one CVI-NHL devoid of a BCL-6 rearrangement. All CVI-NHL scored negative for genetic lesions of BCL-2, p53, c-MYC, REL as well as for viral infection by EBV and HHV-8. Overall, these data indicate that: similarly to other immunodeficiency-related NHL, involvement of BCL6 occurs frequently also in CVI-NHL; and because BCL-6 mutations are acquired by B cells during GC transit, their occurrence in CVI-NHL suggest that these lymphomas are histogenetically related to GC B cells.     

Genetic analysis of chromosome 13 deletions in BCR/ABL negative chronic myeloproliferative disorders

Chromosomal deletions of band 13q14 occur recurrently in BCR/ABL negative chronic myeloproliferative disorders (CMPD), including myelosclerosis with myeloid metaplasia (MMM), polycythemia vera (PV), essential thrombocythemia (ET), juvenile chronic myeloid leukemia (JCML), and the so-called BCR/ABL ^? chronic myeloid leukemia (CML). The RB1 tumor suppressor locus, mapping to 13q14, has long since been hypothesized as the important gene. In this report, we have determined the frequency of 13q14 deletions at the molecular level in a large panel of BCR/ABL ^? CMPD at different disease stages and performed a detailed genetic analysis of gross rearrangements/deletions and point mutations of the RBI gene in these disorders. Our data show that molecular deletions of 13q14 are detected in a relatively large fraction of BCR/ABL ^? CMPD (38%), that they appear to be more frequent in MMM than in other BCR/ABL ^? CMPD, and that they may be present at diagnosis or occur during blastic evolution of the neoplasia. The RBI gene displayed a germline configuration in all BCR/ABL ^? CMPD tested, suggesting that 13q14 deletions in these disorders affect a tumor suppressor locus distinct from RB1.     

Distribution of TP53 mutations among acute leukemias with MLL rearrangements

Acute leukemias carrying MLL rearrangements are characterized by a high degree of clinical and immunologic heterogeneity, as demonstrated by variability in their immunophenotype, consistent with lymphoid or myeloid/monoblastic derivation, as well as their occurrence in distinct age groups from infancy to adulthood. Recently, it was shown that inactivation of the TP53 tumor suppressor gene occurs frequently in cases of acute lymphoblastic leukemia carrying MLL rearrangements. In order to assess the extent of TP53 inactivation throughout the immunophenotypic and clinical spectrum of MLL⁺ acute leukemias, we tested for TP53 mutations 29 cases of MLL⁺ acute leukemias displaying lymphoid (13 cases) or myeloid/monoblastic (16 cases) features and belonging to different age groups. Mutations were detected in 6/16 myeloid/monoblastic cases and in 3/13 lymphoid cases. Among myeloid/monoblastic leukemias, the TP53 mutations occurred in 3/4 infants, but only in 3/16 cases in other age groups. Overall, our data suggest that (1) TP53 inactivation is a relatively common event in leukemias with MLL rearrangements irrespective of the leukemic phenotype and of the patients' age; (2) at least two genetic lesions (i.e., MLL rearrangement and TP53 mutation) have accumulated in the short time (few weeks after the birth or conception of the child) corresponding to the development of acute leukemias of infancy. Genes Chromosom Cancer 15:48–53 (1996). © 1996 Wiley-Liss, Inc.