Advantages and disadvantages of mouse models of chronic lymphocytic leukemia in drug discovery.

Published on Jun 11, 2021in Expert Opinion on Drug Discovery4.887
· DOI :10.1080/17460441.2021.1935860
Heribert Playa-Albinyana1
Estimated H-index: 1
,
Fabian Arenas2
Estimated H-index: 2
,
Dolors Colomer88
Estimated H-index: 88
(University of Barcelona)
Sources
Abstract
Chronic lymphocytic leukemia (CLL) is a lymphoid malignancy characterized by the proliferation and accumulation of mature CD5+ B cells in the peripheral blood (PB), bone marrow (BM) and lymphoid ti...
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#1Gema Perez-Chacon (CSIC: Spanish National Research Council)H-Index: 15
#2Juan M. Zapata (CSIC: Spanish National Research Council)H-Index: 48
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) is a heterogeneous disease consisting of at least two separate subtypes, based on the mutation status of the immunoglobulin heavy chain variable gene (IGHV) sequence. Exposure to antigens seems to play a role in malignant transformation and in the selection and expansion of more aggressive CLL clones. Furthermore, a biased usage of particular IGHV gene subgroups and the existence of stereotyped B-cell receptors (BCRs) are distin...
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#1Piers E.M. Patten ('KCL': King's College London)H-Index: 17
#2Gerardo Ferrer (The Feinstein Institute for Medical Research)H-Index: 14
Last. Nicholas Chiorazzi (Hofstra University)H-Index: 77
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Patient-derived xenograft models of chronic lymphocytic leukemia (CLL) can be created using highly immunodeficient animals, allowing analysis of primary tumor cells in an in vivo setting. However, unlike many other tumors, CLL B lymphocytes do not reproducibly grow in xenografts without manipulation, proliferating only when there is concomitant expansion of T cells. Here we show that in vitro pre-activation of CLL-derived T lymphocytes allows for a reliable and robust system for primary CLL cell...
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#1Melanie Märklin (University of Tübingen)H-Index: 8
#2Alexander R. Fuchs (University of Tübingen)H-Index: 2
Last. Martin Müller (University of Tübingen)H-Index: 76
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Most patients with chronic lymphocytic leukemia (CLL) exhibit an indolent disease course and unresponsive B cell receptors (BCRs) exemplified by an anergic phenotype of their leukemic cells. In up to 5% of patients, CLL transforms from an indolent subtype to an aggressive form of B cell lymphoma (Richter’s syndrome), which is associated with worse disease outcome and severe downregulation of NFAT2. Here we show that ablation of the tyrosine kinase LCK, which has previously been characterized as ...
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#1Julio DelgadoH-Index: 42
#2Ferran NadeuH-Index: 15
Last. Elias Campo (University of Barcelona)H-Index: 150
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Chronic lymphocytic leukemia is a well-defined lymphoid neoplasm with very heterogeneous biological and clinical behavior. The last decade has been remarkably fruitful in novel findings elucidating multiple aspects of the pathogenesis of the disease including mechanisms of genetic susceptibility, insights into the relevance of immunogenetic factors driving the disease, profiling of genomic alterations, epigenetic subtypes, global epigenomic tumor cell reprogramming, modulation of tumor cell and ...
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#1Sarah Decker (University of Freiburg)H-Index: 6
#2Anabel Zwick (Saarland University)H-Index: 4
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Preclinical drug development for human chronic lymphocytic leukemia (CLL) requires robust xenograft models recapitulating the entire spectrum of the disease, including all prognostic subgroups. Current CLL xenograft models are hampered by inefficient engraftment of good prognostic CLLs, overgrowth with co-transplanted T cells, and the need for allogeneic humanization or irradiation. Therefore, we aimed to establish an effective and reproducible xenograft protocol which allows engraftment of all ...
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#2Kerry A. Rogers (OSU: Ohio State University)H-Index: 15
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Purpose: Aberrant Myc expression is a major factor in the pathogenesis of aggressive lymphoma, and these lymphomas, while clinically heterogeneous, often are resistant to currently available treatments and have poor survival. Myc expression can also be seen in aggressive lymphomas that are observed in the context of CLL, and we sought to develop a mouse model that could be used to study therapeutic strategies for aggressive lymphoma in the context of CLL. Experimental Design: We crossed the Eµ-T...
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#1Nadja Zaborsky (Seattle Children's Research Institute)H-Index: 10
#2Franz Josef Gassner (Seattle Children's Research Institute)H-Index: 8
Last. Alexander Egle (Seattle Children's Research Institute)H-Index: 33
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The TCL1 mouse model is widely used to study pathophysiology, clonal evolution, and drug sensitivity or resistance of chronic lymphocytic leukemia (CLL). By performing whole exome sequencing, we present the genetic landscape of primary tumors from TCL1 mice and of TCL1 tumors serially transplanted into wild-type recipients to mimic clonal evolution. We show that similar to CLL patients, mutations in mice are frequently subclonal and heterogenous among different primary TCL1 mice. We further desc...
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#1Shanye Yin (Harvard University)H-Index: 8
#2Rutendo Gambe (Harvard University)H-Index: 4
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Summary SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remains elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. These CLL-like cells show genome instability and dysr...
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#1Tiziana Vaisitti (UNITO: University of Turin)H-Index: 27
#2Esteban Braggio (Mayo Clinic)H-Index: 36
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Richter9s syndrome (RS) represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemo-immunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft models of RS, RS9737 and RS1...
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#1Michael Hallek (University of Cologne)H-Index: 124
#2Bruce D. Cheson (Georgetown University)H-Index: 83
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The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by physicians and investigators caring for patients with CLL. Recent advances including the discovery of the genomic landscape of the disease, the development of genetic tests with prognostic relevance, and the detection of minimal residual disease (MRD), coupled with the increased availability of novel targeted agents with impressi...
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