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Transgenic mouse model of IgM⁺ lymphoproliferative disease mimicking Waldenstrom macroglobulinemia.

ABSTRACT: Waldenström macroglobulinemia (WM) is a low-grade incurable immunoglobulin M⁺ (IgM⁺) lymphoplasmacytic lymphoma for which a genetically engineered mouse model of de novo tumor development is lacking. On the basis of evidence that the pro-inflammatory cytokine, interleukin 6 (IL6), and the survival-enhancing oncoprotein, B cell leukemia 2 (BCL2), have critical roles in the natural history of WM, we hypothesized that the enforced expression of IL6 and BCL2 in mice unable to perform immunoglobulin class switch recombination may result in a lymphoproliferative disease that mimics WM. To evaluate this possibility, we generated compound transgenic BALB/c mice that harbored the human BCL2 and IL6 transgenes, E?SV-BCL2-22 and H2-L^d-hIL6, on the genetic background of activation-induced cytidine deaminase (AID) deficiency. We designated these mice BCL2⁺IL6⁺AID^- and found that they developed-with full genetic penetrance (100% incidence) and suitably short latency (93 days median survival)-a severe IgM⁺ lymphoproliferative disorder that recapitulated important features of human WM. However, the BCL2⁺IL6⁺AID^- model also exhibited shortcomings, such as low serum IgM levels and histopathological changes not seen in patients with WM, collectively indicating that further refinements of the model are required to achieve better correlations with disease characteristics of WM.

SUBMITTER: Tompkins VS

PROVIDER: S-EPMC5148059 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Transgenic mouse model of IgM+ lymphoproliferative disease mimicking Waldenström macroglobulinemia.

Tompkins V S VS Sompallae R R Rosean T R TR Walsh S S Acevedo M M Kovalchuk A L AL Han S-S SS Jing X X Holman C C Rehg J E JE Herms S S Sunderland J S JS Morse H C HC Janz S S

Blood cancer journal 20161104 11

Waldenström macroglobulinemia (WM) is a low-grade incurable immunoglobulin M+ (IgM+) lymphoplasmacytic lymphoma for which a genetically engineered mouse model of de novo tumor development is lacking. On the basis of evidence that the pro-inflammatory cytokine, interleukin 6 (IL6), and the survival-enhancing oncoprotein, B cell leukemia 2 (BCL2), have critical roles in the natural history of WM, we hypothesized that the enforced expression of IL6 and BCL2 in mice unable to p ...[more]

PMID: 27813533

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Project description:We analyzed MYD88 and CXCR4 mutation status of 260 patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance using allele-specific real time quantitative polymerase chain reaction and Sanger sequencing, respectively. A subgroup of 119 patients was further studied with next-generation sequencing of 11 target genes (MYD88, CXCR4, ARID1A, KMT2D, NOTCH2, TP53, PRDM1, CD79B, TRAF3, MYBBP1A, and TNFAIP3). MYD88 (L265P) was found at diagnosis in 91% of patients with Waldenström macroglobulinemia and in 60% of patients with IgM monoclonal gammopathy of undetermined significance using allele-specific polymerase chain reaction analysis. MYD88 mutations other than the classical L265P (V217F, S219C and M232T) were found in four cases by next-generation sequencing. Waldenström macroglobulinemia patients with wild-type MYD88 had a distinct clinical phenotype characterized by less bone marrow infiltration (P=0.01) and more frequent extramedullary involvement (P=0.001) compared to patients with mutated MYD88 Patients with wild-type MYD88 did not show additional mutations in the other target genes. CXCR4 mutations were found by Sanger sequencing in 22% of patients with Waldenström macroglobulinemia. With next-generation sequencing, a CXCR4 mutation was detected in 23% of patients with Waldenström macroglobulinemia and 9% of those with IgM monoclonal gammopathy of undetermined significance. Asymptomatic Waldenström macroglobulinemia patients harboring a CXCR4 mutation had a shorter treatment-free survival (51 months) than that of patients with wild-type CXCR4 (median not reached) (P=0.007). Analysis of variant allele frequencies indicated that CXCR4 mutations were present in the dominant clone in the majority of cases. Recurrent somatic mutations of KMT2D were found in 24% of patients with Waldenström macroglobulinemia and 5% of patients with IgM monoclonal gammopathy of undetermined significance and were primarily subclonal.

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Transgenic mouse model of IgM⁺ lymphoproliferative disease mimicking Waldenstrom macroglobulinemia.

Publications

Transgenic mouse model of IgM<sup>+</sup> lymphoproliferative disease mimicking Waldenström macroglobulinemia.

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Dataset Information

Transgenic mouse model of IgM+ lymphoproliferative disease mimicking Waldenstrom macroglobulinemia.

Publications

Transgenic mouse model of IgM<sup>+</sup> lymphoproliferative disease mimicking Waldenström macroglobulinemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Transgenic mouse model of IgM⁺ lymphoproliferative disease mimicking Waldenstrom macroglobulinemia.