Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies

Leskov, Ilya; Pallasch, Christian P.; Drake, Adam; Iliopoulou, Bettina P.; Souza, Amanda; Shen, Ching-Hung; Schweighofer, Carmen D.; Abruzzo, Lynne V.; Frenzel, Lukas P.; Wendtner, Clemens; Hemann, Michael T.; Chen, Jianzhu

doi:10.1038/onc.2012.117

Cited by 46 publications

(43 citation statements)

References 35 publications

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“…These new models have been used to characterize cancer stem cells and other facets of tumour biology 95, 96 , and reports are now appearing on features of the human anti-tumor immune response. Transplantation of primary lung tumors revealed the existence of tumor infiltrating effector memory T cells that could be activated by administration of human IL-12 97 .…”

Section: Tumour Immunologymentioning

confidence: 99%

Humanized mice for immune system investigation: progress, promise and challenges

et al. 2012

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Preface Significant advances in our understanding of the in vivo functions of human cells, tissues and immune systems have resulted from the development of mouse strains that are based on severely immunodeficient mice expressing mutations in the interleukin-2 (IL-2) receptor common γ-chain locus. These mouse strains support the engraftment of a functional human immune system and permit detailed analysis of human immune biology, development and functions. In this Review, we discuss recent advances in the development of humanized mice, the lessons learned, the remaining challenges and the promise of using humanized mice for the in vivo study of human immunology.

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Section: Tumour Immunologymentioning

confidence: 99%

Humanized mice for immune system investigation: progress, promise and challenges

et al. 2012

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“…We recently developed a treatment refractory humanized mouse model of B-cell lymphoma/leukemia amenable to treatment with therapeutic antibodies (Leskov et al, 2013). Here, by utilizing this humanized model, we identify the bone marrow as a treatment refractory niche and the leukemia-macrophage interaction as a decisive determinant of antibody-mediated toxicity.…”

Section: Introductionmentioning

confidence: 99%

Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy

Pallasch

Leskov

Braun

et al. 2014

Cell

156

160

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Therapy-resistant microenvironments represent a major barrier towards effective elimination of disseminated malignancies. Here, we show that select microenvironments can underlie resistance to antibody-based therapy. Using a humanized model of treatment-refractory B-cell leukemia, we find that infiltration of leukemia cells into the bone marrow rewires the tumor microenvironment to inhibit engulfment of antibody-targeted tumor cells. Resistance to macrophage-mediated killing can be overcome by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, the nitrogen mustard cyclophosphamide induces an acute secretory activating phenotype (ASAP), releasing CCL4, IL8, VEGF and TNFα from treated tumor cells. These factors induce macrophage infiltration and phagocytic activity in the bone marrow. Thus, the acute induction of stress-related cytokines can effectively target cancer cells for removal by the innate immune system. This synergistic chemo-immunotherapeutic regimen represents a potent strategy for using conventional anti-cancer agents to alter the tumor microenvironment and promote the efficacy of targeted therapeutics.

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“…The cooperating effects of MYC and BCL2 in lymphomagenesis have been shown in many studies. [4][5][6][7][8][9][10][11][12][13][14] Numerous case series of MYC/BCL2 double-hit lymphoma are reported in the literature. [15][16][17][18][19][20][21][22][23][24] MYC/ BCL2 DHLs represent B10% of all lymphomas that otherwise resemble diffuse large B-cell lymphoma (DLBCL).…”

mentioning

confidence: 99%

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

Seegmiller

Lin

et al. 2015

Modern Pathology

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Large B-cell lymphomas with IGH@BCL2 and MYC rearrangement, known as double-hit lymphoma (DHL), are clinically aggressive neoplasms with a poor prognosis. Some large B-cell lymphomas have concurrent abnormalities of MYC and BCL2 other than coexistent translocations. Little is known about patients with these lymphomas designated here as atypical DHL. We studied 40 patients of atypical DHL including 21 men and 19 women, with a median age of 60 years. Nine (23%) patients had a history of B-cell non-Hodgkin lymphoma. There were 30 diffuse large B-cell lymphoma (DLBCL), 7 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and 3 DLBCL with coexistent follicular lymphoma. CD10, BCL2, and MYC were expressed in 28/39 (72%), 33/35 (94%), and 14/20 (70%) cases, respectively. Patients were treated with standard (n ¼ 14) or more aggressive chemotherapy regimens (n ¼ 17). We compared the atypical DHL group with 76 patients with DHLand 35 patients with DLBCL lacking MYC and BCL2 abnormalities. The clinicopathologic features and therapies were similar between patients with atypical and typical DHL. The overall survival of patients with atypical double-hit lymphoma was similar to that of patients with double-hit lymphoma (P ¼ 0.47) and significantly worse than that of patients with DLBCL with normal MYC and BCL2 (P ¼ 0.02). There were some minor differences. Cases of atypical double-hit lymphoma more often have DLBCL morphology (Po0.01), less frequently expressed CD10 (Po0.01), and patients less often had an elevated serum lactate dehydrogenase level (P ¼ 0.01). In aggregate, these results support expanding the category of MYC/ BCL2 DHL to include large B-cell lymphomas with coexistent MYC and BCL2 abnormalities other than concurrent translocations.

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Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies

Cited by 46 publications

References 35 publications

Humanized mice for immune system investigation: progress, promise and challenges

Humanized mice for immune system investigation: progress, promise and challenges

Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

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