MALT lymphoma and extranodal diffuse large B-cell lymphoma are targeted by aberrant somatic hypermutation

Abstract

Recently, a novel mechanism introducing genetic instability, termed aberrant somatic hypermutation (ASHM), has been described in diffuse large B-cell lymphoma. To further investigate whether ASHM also occurs in mucosa-associated lymphoid tissue type (MALT) lymphoma, we studied the mutation profile of PIM1, IntroductionExtranodal marginal zone B-cell lymphoma of the mucosaassociated lymphoid tissue type (MALT lymphoma) preferentially arises in the gastrointestinal tract, especially the stomach where it is closely linked to a Helicobacter pylori-induced chronic gastritis. 1,2 In general, MALT lymphoma may affect virtually every organ in the body. 3,4 Because of the interaction between lymphoma cells and mucosal adhesion molecules, 5 MALT lymphomas display an indolent clinical behavior; however, transformation in diffuse large B-cell lymphoma (DLBCL) occurs but, according to the WHO criteria, is considered as a separate entity. 6 Foci of extranodal DLBCL may be seen in MALT lymphoma, termed transformed MALT lymphoma, suggestive of transformation from one to the other entity.MALT lymphomas demonstrate a number of distinct cytogenetic alterations, 7 but a molecular mechanism inducing genetic instability has not been described. In DLBCL somatic hypermutation aberrantly targets the 5Ј sequences of several protooncogenes relevant to lymphomagenesis, including PIM1, PAX5, RhoH/TTF, and cMYC. This phenomenon, termed aberrant somatic hypermutation (ASHM) occurs in over 50% of DLBCL but is rare in indolent lymphomas. 8 Although the molecular mechanism of the SHM is still unknown, studies identified the activation-induced cytidine deaminase (AID) as an absolute requirement for the SHM. 9 The present study was aimed at investigating the role of the aberrant somatic hypermutation in MALT lymphomas and in MALT lymphomas transformed to extranodal DLBCL and to elucidate the role of AID in this process. Materials and methods Materials, diagnoses, and DNA extractionDNA extraction (DNA Mini Kit; Qiagen, Valencia, CA) was performed from formalin-fixed and paraffin-embedded macrodissected tissue containing at least 90% malignant cells. Seventeen MALT lymphoma specimens, 6 of gastric origin and 11 of extragastric origin (2 orbita, 7 parotid gland, 1 thyroid, and 1 soft tissue), and 17 samples of extranodal DLBCL, 10 of gastric origin and 7 of extragastric origin (2 thyroid and 5 parotid gland), and 6 normal controls, including 5 surrounding nonneoplastic tissues samples and one of peripheral blood mononuclear cells were included. All lymphomas were classified according to the WHO classification of lymphoid neoplasms. 6 Attention was made that cases of extranodal DLBCL comprised at least one focus of a low-grade lymphoma component considering these lymphomas as "transformed MALT lymphomas." 10 Immunohistochemistry was performed using monoclonal antibodies to The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate ...

eIF4B Phosphorylation by Pim Kinases Plays a Critical Role in Cellular Transformation byAblOncogenes

“…On the basis of their oncogenic potential, the Pim kinase family is emerging as an important new target for drug discovery (46). However, malignant transformation of lymphoid and myeloid cells involves the dysregulation or mutation of genes including PI3K/Akt pathway and Pim family (14,47). The Akt and Pim kinases produce parallel oncogenic signals and share many molecular targets normally involved in regulating the cell proliferation and survival.…”

Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells

“…Malignant transformation of lymphoid and myeloid cells involves the dysregulation or mutation of genes including PI3K/AKT pathway and Pim families that are normally involved in regulating the proliferation and survival of hematopoietic cells (Pasqualucci et al, 2001;Amaravadi and Thompson, 2005;Deutsch et al, 2007;Horn et al, 2008). These altered genes cooperate to endow the transformed cells with cytokine-independent growth.…”

Chronic inflammatory disease, lymphoid tissue neogenesis and extranodal marginal zone B-cell lymphomas

“…138 Finally, there is little dispute that t(3;14) is prevalent in a subset of DLBCLs, with extranodal presentation and having the activated B cell-like (ABC) expression profile. 135,137,152 Although the precise frequencies of transition of the various low-grade MZBCLs into DLBCLs are not clear in literature, ample evidence exists that MZBCLs can transform particularly into ABC-type DLBCLs rather than into GC-type DLBCLs: (i) trisomy 3 has been observed as a characteristic alteration in both MZBCLs and ABCtype DLBCLs; 49,51,153 (ii) MZBCLs with high nuclear FOX-P1 were documented to progress into ABC-type DLBCLs; 138 (iii) the majority of genomic alterations in t(11;18)-negative MZBCLs are also found in ABC-type DLBCLs; 49,153 (iv) both MZBCLs and ABC-type DLBCLs are characterized by constitutive NF-κB signaling; 154,155 (v) DLBCLs which still contain a low-grade lymphoma component are mostly of the ABC type; 156 (vi) primary gastrointestinal DLBCLs show a similar expression profile as gastrointestinal MALT lymphoma; 157 and (vii) the majority of rheumatoid arthritis-associated DLBCLs are of the ABC type. 158 The molecular mechanisms underlying MZBCL progression are as yet ill-defined.…”

“…However, immunohistochemical expression analyses showed that AID is detectable only in a minority of the cases. 75,156 Accordingly, several investigators demonstrated variable, but generally low AID mRNA expression levels in MALT lymphomas. 156,162,163 On the other hand, in ~50% of DLBCL, several proto-oncogenes, including PIM1, PAX5, RhoH/TTF and cMYC are targeted by aberrant SHM.…”

“…75,156 Accordingly, several investigators demonstrated variable, but generally low AID mRNA expression levels in MALT lymphomas. 156,162,163 On the other hand, in ~50% of DLBCL, several proto-oncogenes, including PIM1, PAX5, RhoH/TTF and cMYC are targeted by aberrant SHM. Sequence analysis of MALT lymphomas revealed that 75% of low-grade MZBCLs and 100% of low-grade MZBCLs with a DLBCL component contained mutations in one or more of these oncogenes.…”