Transgenic mouse model of IgM+ lymphoproliferative disease mimicking Waldenström macroglobulinemia

Tompkins, VS; Sompallae, Ramakrishna; Tr, Rosean; Walsh, Susan A.; Acevedo, Michael R.; Kovalchuk, Alexander L.; Han, Seong‐Su; Jing, Xuefang; Holman, Carol J.; Je, Rehg; Herms, Stefan; Js, Sunderland; Hc, Morse; Janz, Siegfried

doi:10.1038/bcj.2016.95

Cited by 4 publications

(6 citation statements)

References 59 publications

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“…18,19 In a different study, it was reported that BCL2 1/2 IL6 1/2 AID 2/2 mice develop an LPD-mimicking LPL/ WM; however, the disease was also polyclonal and transcriptionally resembled chronic lymphocytic leukemia more than WM. 42 Moreover, IgM expression was artificially induced in this model by knocking out both alleles of AID, an enzyme that plays crucial roles in class-switching but is unaltered in tumor cells from LPL/WM patients. 42 Even though these models provide new insight into the pathogenesis of LPL/WM and DLBCL, a bona fide and clinically relevant murine model of human LPL/WM does not yet seem to exist.…”

Section: Discussionmentioning

confidence: 99%

“…42 Moreover, IgM expression was artificially induced in this model by knocking out both alleles of AID, an enzyme that plays crucial roles in class-switching but is unaltered in tumor cells from LPL/WM patients. 42 Even though these models provide new insight into the pathogenesis of LPL/WM and DLBCL, a bona fide and clinically relevant murine model of human LPL/WM does not yet seem to exist.…”

Section: Discussionmentioning

confidence: 99%

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Human MYD88L265P is insufficient by itself to drive neoplastic transformation in mature mouse B cells

et al. 2019

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MYD88 L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although inhibition of the mutated MYD88 pathway has an adverse impact on LPL/WM and DLBCL cell survival, its role in lymphoma initiation remains to be clarified. We show that in mice, human MYD88L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, increased number of mast cells in the bone marrow, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL. Murine findings regarding differences in the pattern of MYD88 staining and immune infiltrates in the bone marrows of MYD88 wild-type (MYD88WT) and MYD88L265P mice are recapitulated in the human setting, which provides insight into LPL/WM pathogenesis. Furthermore, histologic transformation to DLBCL is associated with acquisition of secondary genetic lesions frequently seen in de novo human DLBCL as well as LPL/WM-transformed cases. These findings indicate that, although the MYD88L265P mutation might be indispensable for the LPL/WM phenotype, it is insufficient by itself to drive malignant transformation in B cells and relies on other, potentially targetable cooperating genetic events for full development of lymphoma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human MYD88L265P is insufficient by itself to drive neoplastic transformation in mature mouse B cells

et al. 2019

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“…Crossing Myd88 p.L252P mice to the Balb/c background may promote IgM MGUS and WM as aged Balb/c mice have higher levels of IgM rather than IgG (44). Compound transgenic Balb/c mice that harbor the human BCL2 and IL6 transgenes and lack the Aid gene developed, with 100% incidence and short latency (93 days median survival), a severe IgM þ lymphoproliferative disorder that recapitulated many features of human WM (45). NF-kB, STAT3, and MAPK/ERK are activated, yet the Myd88 gene is not somatically mutated in lymphomas developed in aged mice (45).…”

Section: Functional Consequences Of Myd88 L265p Mutationmentioning

confidence: 99%

MYD88 L265P Mutation in Lymphoid Malignancies

Deng

et al. 2018

Cancer Research

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Next-generation sequencing has revealed cancer genomic landscapes, in which over 100 driver genes that, when altered by intragenic mutations, can promote oncogenesis. is a driver gene found in hematologic B-cell malignancies. A missense mutation (L265P) changing leucine at position 265 to proline in MYD88 is found in ∼90% of Waldenström macroglobulinemia (WM) cases and in significant portions of activated B-cell diffuse large B-cell lymphomas and IgM monoclonal gammopathy of undetermined significance. Few cancers such as WM have a single amino acid substitution in one gene like MYD88 L265P that occurs in ∼90% of cases, making WM paradigmatic for study of a single causative mutation in oncogenesis. In this review, we summarize the frequency and cancer spectrum of MYD88 L265P and its downstream effects in lymphoid cancers. Malignant B cells with MYD88 L265P are likely transformed from IgM-producing B cells either in response to T-cell-independent antigens or in response to protein antigens before class switching. We also discuss therapeutic strategies that include targeting Bruton tyrosine kinase and other kinases, interfering with the assembly of MYD88 and its interacting partners, and L265P-specific peptide-based immunotherapy. .

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“…To that end, we generated compound transgenic BALB/c (C) mice that harbored the human BCL2 transgene, EμSV-BCL2-22 [4] , and the human IL6 transgene, H2-L d -hIL6 [5,6] , on the genetic background of activationinduced cytidine deaminase (AID) deficiency [7] . We found that mice of this sort developed IgM + LPL-like tumors with full genetic penetrance (100% incidence) and relatively short onset (93 days median) [3] . In the course of these studies, we also made the surprising discovery that AID deficiency had an opposing impact on tumorigenesis: it accelerated BCL2-driven lymphoma but inhibited IL6-driven lymphoma.…”

Section: Introductionmentioning

confidence: 80%

“…We recently reported on the development of a GEMM of human Waldenström macroglobulinemia (WM)-a low-grade incurable IgM + lymphoplasmacytic lymphoma (LPL) for which a laboratory animal model of de novo tumor development is lacking [3] . Based on a large body of evidence that the proinflammatory cytokine, interleukin 6 (IL-6), and the survival-enhancing oncoprotein, B-cell leukemia 2 (BCL-2), play critical roles in the natural history of WM, we decided to evaluate whether the enforced expression of BCL-2 and IL-6 in mice unable to perform immunoglobulin class switch recombination may result in IgM + B-cell tumors that mimic WM.…”

Section: Introductionmentioning

confidence: 99%

Opposing impact of AID deficiency on BCL-2 and IL-6 driven B-lymphoma development in BALB/c mice

Gu¹,

Jing²,

Yang³

et al. 2017

Blood and Genomics

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Activation-induced cytidine deaminase(AID), an essential enzymatic activity required for somatic hypermutation and immunoglobulin class switch recombination in the course of normal B-lymphocyte development, has been implicated in the initiation and promotion of malignant B-cell tumors by virtue of a complex mechanism that includes the generation of oncogene-activating genomic rearrangements and the introduction of point mutations in cancer genes. Here, we use transgenic mouse models of B-cell lymphoma driven by the pro-inflammatory cytokine, interleukin 6 (IL-6), or the survival-enhancing oncoprotein, B-cell leukemia 2 (BCL-2), to evaluate the impact of loss of AID on neoplastic B-cell development. We show that AID deficiency accelerates BCL-2 induced lymphoma but delays IL-6 induced lymphoma. This led us to conclude that AID may function as tumor suppressor or tumor promoter, depending on the genetic context. Elucidating the mechanism of AID's dual function during malignant B-cell transformation may be important for new approaches to tumor treatment and prevention. Keywords: genetically engineered mouse model (GEMM) of human cancer, B-cell leukemia 2 (BCL-2), interleukin 6 (IL-6), activation-induced cytidine deaminase (AID)

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Transgenic mouse model of IgM+ lymphoproliferative disease mimicking Waldenström macroglobulinemia

Cited by 4 publications

References 59 publications

Human MYD88L265P is insufficient by itself to drive neoplastic transformation in mature mouse B cells

Human MYD88L265P is insufficient by itself to drive neoplastic transformation in mature mouse B cells

MYD88 L265P Mutation in Lymphoid Malignancies

Opposing impact of AID deficiency on BCL-2 and IL-6 driven B-lymphoma development in BALB/c mice

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