CD44 activation in mature B-cell malignancies by a novel recurrent IGH translocation

Abstract

Using inverse polymerase chain reaction, we identified CD44, located on chromosome 11p13, as a novel translocation partner of IGH in 9 of 114 cases of gastric, nongastric extranodal, follicular, and nodal diffuse large B-cell lymphoma (DLBCL). Notably, these translocations involving IGHS were detected in follicular lymphomas and exclusively in germinal center IntroductionMature B-cell non-Hodgkin lymphomas (NHLs) are often associated with chromosomal translocations involving IGH at chromosome band 14q32. 1-5 V(D)J rearrangement and class switch recombination (CSR) are IG rearrangement processes that occur during B-cell development. [6][7][8][9] In CSR, DNA breakage is mediated by activation-induced cytidine deaminase in the germinal centers (GCs) of secondary follicles. 10,11 Any aberrant rearrangement during the DNA breakage and repair processes composed of V(D)J rearrangement and CSR may consequently generate a chromosomal translocation. 12,13 IGH translocations contribute to the pathogenesis of B-cell lymphomas via deregulated expression of the genes located at the partner chromosome locus partly because of the presence of potent B cell-specific transcriptional enhancers within the IGH gene locus. [1][2][3][4][5] Gastric B-cell lymphomas usually exhibit chromosomal translocations involving IGH. 14-16 Molecular cloning of IGH translocation breakpoints has been successfully used to identify novel cancerrelated genes in B-cell lymphomas. 17,18 In this study, we used inverse polymerase chain reaction (PCR) 18 to identify a novel translocation involving the 5Ј S region of the IGH gene (IGHS) and CD44 (located at chromosome 11p13) in gastric as well as other mature B-cell NHLs. Functional studies suggest a possible pathogenic role of this IGHS/CD44 translocation in mature B-cell malignancies. Methods Detection of translocations involving the IGHS by inverse PCRGenomic DNA extracted from frozen sections of tumor specimens from gastric 19 and other mature B-cell NHL cases (supplemental Table 1, available on the Blood website; see the Supplemental Materials link at the top of the online article) was digested with HindIII, and long-distance inverse PCR was performed to detect translocations involving the IGHS region using the primers SAE/JXE, followed by SAI/JXI 18 (supplemental Table 2). Overexpression of CD44⌬Ex1-GFP tagged protein in transfected BJAB cellsCD44⌬Ex1 (CD44 variant mRNA lacking exon 1) and CD44s (standard form; wild-type) cDNAs were amplified by reverse-transcribed (RT)-PCR (supplemental Table 2) from total RNA extracted from a case of gastric lymphoma with the IGHS/CD44 translocation (GL47) and from the peripheral blood lymphocytes of a healthy volunteer; they were then cloned For personal use only. on April 29, 2019. by guest www.bloodjournal.org From in-frame with green fluorescent protein (GFP) at the C-terminus of the pmaxFP-Green-N vector (Amaxa) and transfected into the CD44 Ϫ GC B cell-like (GCB)-diffuse large B-cell lymphoma (DLBCL) cell line BJAB by nucleofection (Amaxa). The subcellular loca...

Peripheral blood involvement in patients with follicular lymphoma: a rare disease manifestation associated with poor prognosis

“…This suggests that, in FL‐LP, cell surface CD54 could be cleaved and released as its soluble form, which would be consistent with the poorer prognosis of these patients. Recently, an enhanced proliferation rate and clonogenic capacity was found in cell lines with ectopic CD44 expression (Higashi et al , ; Hu et al , ). In our study, CD44 was also found to be more frequently expressed in patients with FL‐LP.…”

Epigenetic regulation of CD44in Hodgkin and non-Hodgkin lymphoma

“…CD44 hypermethylation resulting in gene silencing has already been reported for other cancer types like prostate cancer and neuroblastoma [20-22]. Recently, CD44 has been shown to be a novel translocation partner of IGH in mature B-cell malignancies resulting in overexpression of CD44 lacking exon 1 [23]. …”

Identification of IGHCδ–BACH2 fusion transcripts resulting from cryptic chromosomal rearrangements of 14q32 with 6q15 in aggressive B‐cell lymphoma/leukemia

“…These rearrangements are erroneous byproducts of the physiological IGH recombination that occurs in normal B cells (Kuppers and Dalla-Favera, 2001). Furthermore, partner genes of IGH translocation are frequently implicated in B-cell differentiation (e.g., BCL6, IRF4, PAX5, MYC, and CD44), germinal center formation (e.g., BCL6), apoptosis (e.g., BCL2 and MALT1), and cell cycle progression (e.g., MYC, CCND1, CCND3, and CCNE1) (Willis and Dyer, 2000;Lossos, 2005;Hu et al, 2010). Hence, identifying partner genes in IGH translocation will facilitate the elucidation of developmental mechanisms involved in B-cell malignancies and may help to unravel the complexities of B lymphocyte differentiation.…”