Screening for mutations of Bcl10 in leukaemia

Abstract

The Bcl10 gene was identified through characterization of the t(1;14)(p22;q32) associated with mucosa‐associated lymphoid tissue (MALT) lymphoma. Bcl10 is implicated in the regulation of apoptosis and has been reported to be mutated in other subtypes of non‐Hodgkin's B‐cell lymphoma (B‐NHL) and leukaemic cell lines, raising the possibility that its deregulation could be implicated in other forms of haematological malignancy. We screened 226 cases, including 123 acute myeloid leukaemia (AML), 50 acute lymphoblastic leukaemia (ALL), 20 chronic myeloid leukaemia (CML), 10 chronic lymphocytic leukaemia–prolymphocytic leukaemia (CLL/PLL) and 23 cases with 1p abnormalities, for Bcl10 mutations by reverse transcription polymerase chain reaction–single‐stranded conformation polymorphism (RT‐PCR/SSCP). Three known polymorphisms and two common splice variants were identified; however, no mutations were detected. One splice variant led to a 33‐bp in frame deletion, whereas the other caused a 16‐bp deletion predicting C‐terminal truncation of Bcl10. However, both splice variants were also detected in normal bone marrow, suggesting that they are unlikely to be of pathogenetic significance. Furthermore, Southern blot analysis revealed no rearrangements of Bcl10 among 16 ALL and 11 cases of haematological malignancy with 1p abnormalities. Our results suggest that mutation of the Bcl10 gene as a mechanism of tumorigenesis is not associated with leukaemia.

BCL10 mutation does not represent an important pathogenic mechanism in gastric MALT-type lymphoma, and the presence of the API2-MLT fusion is associated with aberrant nuclear BCL10 expression

“…[1][2][3] We analyzed a series of gastric MALT-type lymphomas for the occurrence of BCL10 mutations. We detected 3 commonly reported polymorphisms [3][4][5]12 that occurred 12 times in 11 cases (1, 7, and 4 times, respectively, in codons 5, 8, and 213). The polymorphic nature of codon 8 and 213 alterations was further confirmed by the analysis of reactive tissues and matched normal cells of the lymphoma cases.…”

“…The substitution in codon 5 was G to T (GCA Ͼ TCA) (exon 1), causing an amino acid substitution (ALA Ͼ SER) and was previously described by others as a polymorphism. 4,5,12 Analysis on DNA derived from microdissected tumor cell clusters revealed 2 additional differences with the published BCL10 sequence, both single nucleotide substitutions. One of these was found in a tumor cell cluster of case 13.…”

“…Both polymorphisms were reported previously. [3][4][5]12 As analyzed on the DNA extracted from whole tissue sections, the 35 MALT-type lymphoma cases showed a total of 16 differences with the published sequence in 14 cases. Twelve cases showed 1 difference, and 2 cases exhibited 2 differences.…”

“…In addition, because BCL10 mutations were also detected at a high frequency in cell lines derived from male germ cell tumors and mesothelioma without chromosomal rearrangements of the BCL10 locus, it was suggested that BCL10 mutation might represent a common pathogenetic mechanism involved in a variety of solid tumors. 1 In a series of other studies, the occurrence of BCL10 mutation could not be confirmed for lymphoma and other hematologic malignancies or for a wide range of solid tumors [4][5][6][7][8][9][10][11][12][13] ; thus, the role of BCL10 mutation resulting in the loss of tumor suppressor function remains controversial. Moreover, the occurrence of the t(1;14)(p22;q32) in MALT-type lymphoma is not always associated with the presence of BCL10 mutations.…”

BCL10 mutations are irrelevant to its aberrant nuclear localization in nasal NK/T-cell lymphoma

“…The appearance of this splice variant in the tumors but not in the reactive tonsils initially suggested its tumorigenetic role, as proposed in the early publications. 1 However, it has also been reported that this splice variant is present in bone marrow specimens from normal individuals, 8 so it seems likely that the splice variant might be a response to an altered cellular state in the tumor. In case 14, the variant-promoting mutation could be a tumorigenic event.…”