Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice

Abstract

Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1 + Lin − hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas.

Chronic lymphocytic leukemia: Time to go past genomics?

“…Of note, inactivation of MLL2 early in B-cell differentiation (at pro/preB stage, using CD19-Cre) results in a stronger phenotype that when induced at later stage, during the GC (Cg1-Cre) [144]. This may be due a stage specific effect [146] or to the number of cell division required to uncover the consequences of MLL2 inactivation, or both. Similar observations have been reported using BRAFV600E conditional mice since activation of BRAF in progenitor cells and in differentiating B-cells differs, with progenitor activation showing a very strong transformation phenotype [82].…”

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

“…[16][17][18][19] To achieve Tg expression of Fbxl10 in mice, the Flagtagged mouse Fbxl10 cDNA was inserted into the cloning site of the Ly6A/Sca-1 Tg cassette that allows high expression in the HSC compartment 17 (supplemental Figure 1A). We confirmed a .10-fold upregulation of Fbxl10 messenger RNA (mRNA) in Sca-1 1 cells in 2 independent lines (lines 3 and 4) (supplemental Figure 1B), both of which provided similar results in this study (thus, hereafter we refer to mice in both lines as Fbxl10 Tg mice).…”

Dysregulation of the antigen-induced NF-κB signaling pathway in the development of human B-cells lymphomas

“…The most common in ocular adnexa lymphoma is t(14;18)(q32;q21) which was originally found in MALT lymphoma of the liver and skin and involves the placement of the MALT1 gene under the control of the Ig heavy chain enhancer (IGH-MALT1) [112]. Others have been reported including trisomy 3 or 18 occurring most frequently in intestinal and salivary gland MALT lymphoma [113] and, more recently, t(3;14)(p14.1;q32), involving the IGH and forkhead box protein P1 (FOXP1), that was also reported in DLBCL [114]. Forkhead box P1 contains a N-terminal glutamine-rich region, a zinc finger, a leucine zipper, a forkhead and an acid-rich domain.…”