As we search for new treatment modalities and increasingly work to identify mechanisms of action of specific hematological malignancies, murine models are indispensible. There exist several B- and T-cell malignancies, specifically, that still lack effective mouse model systems that mimic human phenotype.  This research topic highlights mouse models used to study hematological malignancies, specifically of the lymphoid lineage. Articles may include comprehensive reviews summarizing existing models of T-cell and B-cell leukemias/lymphomas. Moreover, researchers whom have initiated novel murine models of leukemias/lymphomas may submit original research articles describing their model. Lastly, short communications highlighting potentially effective models, based on primary data are encouraged.

University of Nebraska Omaha

Sidney Kimmel Cancer Center

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Frontiers in Oncology

Hematologic Malignancies

Murine models of leukemia and lymphoma

Editorial on the Research Topic<a href="http://journal.frontiersin.org/researchtopic/4311">Murine Models of Leukemia and Lymphoma</a>Murine models serve as an effective way to mimic the in vivo tumor microenvironmental interactions that take place in patients with leukemias and lymphomas. Specifically, leukemias and lymphomas rely heavily on the surrounding stroma and tissue microenvironmental cytokine and chemokine signals to ensure survival and expansion of tumor cells. Finally, leukemic cells migrate thanks to signals from varying regions of the host, furthering the progression and severity of disease. It is therefore impossible to fully understand such a dynamic relationship between tumor cells and their surrounding microenvironment, and the events to transformation in leukemias and lymphomas without an in vivo, or murine model. While many models have been established, their strengths and weaknesses must be realized in order to best interpret findings from each model and ultimately apply that to the clinic. All of this knowledge is useful in determining the etiology of the tumor cells, the plasticity of them, their relationship with the surrounding microenvironment, diagnostic and prognostic markers, as well as serve as a way to test novel therapeutic regimens.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Editorial: Murine Models of Leukemia and Lymphoma

The role of the tumor microenvironment in leukemias and lymphomas is well established, yet the intricacies of how the malignant cells regulate and influence their non-malignant counterparts remain elusive. For example, chronic lymphocytic leukemia (CLL) is an expansion of malignant CD5+CD19+ B cells, yet the non-malignant T cells play just as large of a role in disease presentation and etiology. Herein, we review the dynamic tumor cell to lymphoid repertoire interactions found in two non-Hodgkin’s lymphoma subtypes: CLL and angioimmunoblastic T-cell lymphoma. We aim to highlight the pivot work done in the murine models which recapitulate these diseases and explore the insights that can be gained from studying the immuno-oncological regulation of non-malignant lymphoid counterparts.

The role of the tumor microenvironment in leukemias and lymphomas is well established, yet the intricacies of how the malignant cells regulate and influence their non-malignant counterparts remain elusive. For example, chronic lymphocytic leukemia (CLL) is an expansion of malignant CD5+CD19+ B cells, yet the non-malignant T cells play just as large of a role in disease presentation and etiology. Herein, we review the dynamic tumor cell to lymphoid repertoire interactions found in two non-Hodgkin’s lymphoma subtypes: CLL and angioimmunoblastic T-cell lymphoma. We aim to highlight the pivot work done in the murine models which recapitulate these diseases and explore the insights that can be gained from studying the immuno-oncological regulation of non-malignant lymphoid counterparts.

Using Murine Models to Investigate Tumor–Lymphoid Interactions: Spotlight on Chronic Lymphocytic Leukemia and Angioimmunoblastic T-Cell Lymphoma

Murine models have been adopted as a significant and powerful tool in the study of cancer. The applications of murine models of cancer are numerous: mechanism discovery, oncogenesis, molecular genetics, microenvironment, metastasis, and therapeutic efficacy. Leukemias and lymphomas are a group of highly heterogeneous hematologic malignancies that affect people of all ages and ethnicities. Leukemia and lymphoma arise from hematopoietic and immune cells and usually spread widely throughout the body. The liquid nature of many of these malignancies, as well as the complex microenvironment from which they arise and their multifaceted genetic basis, has added to the difficulty in generating appropriate and translational models to study them. Murine models of leukemia and lymphoma have made substantial contributions to our understanding of the pathobiology of these disorders in humans. However, while there are many advantages to these models, limitations remain. In this review, we discuss the mouse as a model to study leukemia and lymphoma, and the importance of choosing the correct methodology. Specific examples of murine models of leukemias and lymphomas are provided, with particular attention to those that are highly translational to their human counterpart. Finally, future applications of murine models and potential for better models are discussed.

Murine models have been adopted as a significant and powerful tool in the study of cancer. The applications of murine models of cancer are numerous: mechanism discovery, oncogenesis, molecular genetics, microenvironment, metastasis, and therapeutic efficacy. Leukemias and lymphomas are a group of highly heterogeneous hematologic malignancies that affect people of all ages and ethnicities. Leukemia and lymphoma arise from hematopoietic and immune cells and usually spread widely throughout the body. The liquid nature of many of these malignancies, as well as the complex microenvironment from which they arise and their multifaceted genetic basis, has added to the difficulty in generating appropriate and translational models to study them. Murine models of leukemia and lymphoma have made substantial contributions to our understanding of the pathobiology of these disorders in humans. However, while there are many advantages to these models, limitations remain. In this review, we discuss the mouse as a model to study leukemia and lymphoma, and the importance of choosing the correct methodology. Specific examples of murine models of leukemias and lymphomas are provided, with particular attention to those that are highly translational to their human counterpart. Finally, future applications of murine models and potential for better models are discussed.

Overview of the Use of Murine Models in Leukemia and Lymphoma Research

Dozens of murine models of indolent and aggressive B-cell lymphomas have been generated to date. These include those manifesting chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), as well as xenografts of mantle cell lymphoma (MCL). These models have led to an improved understanding of disease etiology, B-cell biology, immunomodulation, and the importance of the tumor microenvironment. Despite these efforts in CLL, DLBCL, and MCL, considerably little progress toward a model of splenic marginal zone lymphoma (SMZL) has been accomplished. Herein, we describe the similarities and differences between CLL, MCL, and SMZL and highlight effective murine models that mimic disease in the two former, in hopes of informing a potential model of the latter. At the time of writing this review, the precise molecular events of SMZL remain to be determined and a treatment regimen remains to be identified. Therefore, based on the efforts put forth in the B-cell lymphoma field throughout the past three decades, the established role of caveolin-1 in B- and T-cell biology as an oncogene or tumor suppressor, and the recurrent deletion or loss of heterozygosity (LOH) of 7q in many cancers, we make recommendations for a murine model of SMZL.

Dozens of murine models of indolent and aggressive B-cell lymphomas have been generated to date. These include those manifesting chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), as well as xenografts of mantle cell lymphoma (MCL). These models have led to an improved understanding of disease etiology, B-cell biology, immunomodulation, and the importance of the tumor microenvironment. Despite these efforts in CLL, DLBCL, and MCL, considerably little progress toward a model of splenic marginal zone lymphoma (SMZL) has been accomplished. Herein, we describe the similarities and differences between CLL, MCL, and SMZL and highlight effective murine models that mimic disease in the two former, in hopes of informing a potential model of the latter. At the time of writing this review, the precise molecular events of SMZL remain to be determined and a treatment regimen remains to be identified. Therefore, based on the efforts put forth in the B-cell lymphoma field throughout the past three decades, the established role of caveolin-1 in B- and T-cell biology as an oncogene or tumor suppressor, and the recurrent deletion or loss of heterozygosity (LOH) of 7q in many cancers, we make recommendations for a murine model of SMZL.

Murine Models of Splenic Marginal Zone Lymphoma: A Role for Cav1?

Currently, there are 19 different peripheral T-cell lymphoma (PTCL) entities recognized by the World Health Organization; however, ~70% of PTCL diagnoses fall within one of three subtypes [i.e., peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma, and angioimmunoblastic T-cell lymphoma]. PTCL-NOS is a grouping of extra-thymic neoplasms that represent a challenging and heterogeneous subset of non-Hodgkin’s lymphomas. Research into peripheral T-cell lymphomas has been cumbersome as the lack of defining cytogenetic, histological, and molecular features has stymied diagnosis and treatment of these diseases. Similarly, the lacks of genetically manipulated murine models that faithfully recapitulate disease characteristics were absent prior to the turn of the century. Herein, we review the literature concerning existing mouse models for PTLC-NOS, while paying particular attention to the etiology of this heterogeneous disease.

Currently, there are 19 different peripheral T-cell lymphoma (PTCL) entities recognized by the World Health Organization; however, ~70% of PTCL diagnoses fall within one of three subtypes [i.e., peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma, and angioimmunoblastic T-cell lymphoma]. PTCL-NOS is a grouping of extra-thymic neoplasms that represent a challenging and heterogeneous subset of non-Hodgkin&#x2019;s lymphomas. Research into peripheral T-cell lymphomas has been cumbersome as the lack of defining cytogenetic, histological, and molecular features has stymied diagnosis and treatment of these diseases. Similarly, the lacks of genetically manipulated murine models that faithfully recapitulate disease characteristics were absent prior to the turn of the century. Herein, we review the literature concerning existing mouse models for PTLC-NOS, while paying particular attention to the etiology of this heterogeneous disease.

Burrowing through the Heterogeneity: Review of Mouse Models of PTCL-NOS

Over the last 30 years, studies of aberrant DNA methylation in hematologic malignancies have been dominated by the primary focus of understanding promoter hypermethylation. These efforts not only resulted in a better understanding of the basis of epigenetic silencing of tumor suppressor genes but also resulted in approval of hypomethylating agents for the treatment of several malignancies, such as myelodysplastic syndrome and acute myeloid leukemia. Recent advances in global methylation profiling coupled with the use of mouse models suggest that aberrant promoter hypomethylation is also a frequent event in hematologic malignancies, particularly in chronic lymphocytic leukemia (CLL). Promoter hypomethylation affects gene expression and, therefore, may play an important role in disease pathogenesis. Here, we review recent findings and discuss the potential involvement of aberrant promoter hypomethylation in CLL.

Over the last 30 years, studies of aberrant DNA methylation in hematologic malignancies have been dominated by the primary focus of understanding promoter hypermethylation. These efforts not only resulted in a better understanding of the basis of epigenetic silencing of tumor suppressor genes but also resulted in approval of hypomethylating agents for the treatment of several malignancies, such as myelodysplastic syndrome and acute myeloid leukemia. Recent advances in global methylation profiling coupled with the use of mouse models suggest that aberrant promoter hypomethylation is also a frequent event in hematologic malignancies, particularly in chronic lymphocytic leukemia (CLL). Promoter hypomethylation affects gene expression and, therefore, may play an important role in disease pathogenesis. Here, we review recent findings and discuss the potential involvement of aberrant promoter hypomethylation in CLL.

Aberrant Promoter Hypomethylation in CLL: Does It Matter for Disease Development?

Generation of orthotopic xenograft mouse models of leukemia is important to understand the mechanisms of leukemogenesis, cancer progression, its cross talk with the bone marrow microenvironment, and for preclinical evaluation of drugs. In these models, following intravenous injection, leukemic cells home to the bone marrow and proliferate there before infiltrating other organs, such as spleen, liver, and the central nervous system. Moreover, such models have been shown to accurately recapitulate the human disease and correlate with patient response to therapy and prognosis. Thus, various immune-deficient mice strains have been used with or without recipient preconditioning to increase engraftment efficiency. Mice homozygous for the severe combined immune deficiency (SCID) mutation and with non-obese diabetic background (NOD/SCID) have been used in the majority of leukemia xenograft studies. Later, NOD/SCID mice deficient for interleukin 2 receptor gamma chain (IL2Rγ) gene called NSG mice became the model of choice for leukemia xenografts. However, engraftment of leukemia cells without irradiation preconditioning still remained a challenge. In this study, we used NSG mice with null alleles for major histocompatibility complex class I beta2-microglobulin (β2m) called NSG-B2m. This is a first report describing the 100% engraftment efficiency of pediatric leukemia cell lines and primary samples in NSG-B2m mice in the absence of host preconditioning by sublethal irradiation. We also show direct comparison of the engraftment efficiency and growth rate of pediatric acute leukemia cells in NSG-B2m and NOD/SCID mice, which showed 80–90% engraftment efficiency. Secondary and tertiary xenografts in NSG-B2m mice generated by injection of cells isolated from the spleens of leukemia-bearing mice also behaved similar to the primary patient sample. We have successfully engrafted 25 acute lymphoblastic leukemia (ALL) and 5 acute myeloid leukemia (AML) patient samples with distinct cytogenetic characteristics in NSG-B2m mice, with the purpose of generating pediatric ALL and AML xenografts for preclinical evaluation of drugs. Thus, our data support the use of NSG-B2m mouse model for leukemia engraftment and in vivo preclinical drug efficacy studies.

Generation of orthotopic xenograft mouse models of leukemia is important to understand the mechanisms of leukemogenesis, cancer progression, its cross talk with the bone marrow microenvironment, and for preclinical evaluation of drugs. In these models, following intravenous injection, leukemic cells home to the bone marrow and proliferate there before infiltrating other organs, such as spleen, liver, and the central nervous system. Moreover, such models have been shown to accurately recapitulate the human disease and correlate with patient response to therapy and prognosis. Thus, various immune-deficient mice strains have been used with or without recipient preconditioning to increase engraftment efficiency. Mice homozygous for the severe combined immune deficiency (SCID) mutation and with non-obese diabetic background (NOD/SCID) have been used in the majority of leukemia xenograft studies. Later, NOD/SCID mice deficient for interleukin 2 receptor gamma chain (IL2Rγ) gene called NSG mice became the model of choice for leukemia xenografts. However, engraftment of leukemia cells without irradiation preconditioning still remained a challenge. In this study, we used NSG mice with null alleles for major histocompatibility complex class I beta2-microglobulin (β2m) called NSG-B2m. This is a first report describing the 100% engraftment efficiency of pediatric leukemia cell lines and primary samples in NSG-B2m mice in the absence of host preconditioning by sublethal irradiation. We also show direct comparison of the engraftment efficiency and growth rate of pediatric acute leukemia cells in NSG-B2m and NOD/SCID mice, which showed 80–90% engraftment efficiency. Secondary and tertiary xenografts in NSG-B2m mice generated by injection of cells isolated from the spleens of leukemia-bearing mice also behaved similar to the primary patient sample. We have successfully engrafted 25 acute lymphoblastic leukemia (ALL) and 5 acute myeloid leukemia (AML) patient samples with distinct cytogenetic characteristics in NSG-B2m mice, with the purpose of generating pediatric ALL and AML xenografts for preclinical evaluation of drugs. Thus, our data support the use of NSG-B2m mouse model for leukemia engraftment and in vivo preclinical drug efficacy studies.