Dysregulation of PAX5 causes uncommitted B cell development and tumorigenesis in mice

Boast, Brigette; Helian, Kaiyue; Td, Andrews; X, Li; Cho, Vincent; Closa, Adrià; Hj, Sutton; Reed, Joanne H.; Bergmann, H; Cm, Roots; Yabas, Mehmet; Barthel, Nadine; Sa, Omari; Young, Clara; La, Miosge; Eyras, Eduardo; Nutt, Stephen L.; Hein, Nadine; Km, Hannan; Cockburn, Ian A.; Goodnow, Christopher C.; Enders, Anselm

doi:10.1101/2021.01.29.428877

Cited by 3 publications

(1 citation statement)

References 54 publications

(104 reference statements)

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“…A recent study has modelled in mice a single point mutation found in the patient’s PAX5 gene, trying to better recapitulate the human preleukemic stage. In this report, aged Pax5 Y351 */Y351 * mice spontaneously develop B-ALL with 100% penetrance [ 33 ].…”

Section: Mouse Modeling Of Genetic Susceptibility To Childhood Leukemiamentioning

confidence: 99%

Childhood B-Cell Preleukemia Mouse Modeling

Isidro-Hernández

Alemán-Arteaga

Casado-García

et al. 2022

IJMS

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Leukemia is the most usual childhood cancer, and B-cell acute lymphoblastic leukemia (B-ALL) is its most common presentation. It has been proposed that pediatric leukemogenesis occurs through a “multi-step” or “multi-hit” mechanism that includes both in utero and postnatal steps. Many childhood leukemia-initiating events, such as chromosomal translocations, originate in utero, and studies so far suggest that these “first-hits” occur at a far higher frequency than the incidence of childhood leukemia itself. The reason why only a small percentage of the children born with such preleukemic “hits” will develop full-blown leukemia is still a mystery. In order to better understand childhood leukemia, mouse modeling is essential, but only if the multistage process of leukemia can be recapitulated in the model. Therefore, mouse models naturally reproducing the “multi-step” process of childhood B-ALL will be essential to identify environmental or other factors that are directly linked to increased risk of disease.

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Section: Mouse Modeling Of Genetic Susceptibility To Childhood Leukemiamentioning

confidence: 99%

Childhood B-Cell Preleukemia Mouse Modeling

Isidro-Hernández

Alemán-Arteaga

Casado-García

et al. 2022

IJMS

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Lessons from mouse models in the impact of risk factors on the genesis of childhood B-cell leukemia

Casado-García,

Isidro-Hernández,

Alemán-Arteaga

et al. 2023

Front. Immunol.

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B-cell acute lymphoblastic leukemia (B-ALL) stands as the primary contributor to childhood cancer-related mortality on a global scale. The development of the most conventional forms of this disease has been proposed to be conducted by two different steps influenced by different types of risk factors. The first step is led by a genetic insult that is presumably acquired before birth that transforms a healthy cell into a preleukemic one, which is maintained untransformed until the second step takes place. This necessary next step to leukemia development will be triggered by different risk factors to which children are exposed after birth. Murine models that recap the stepwise progression of B-ALL have been instrumental in identifying environmental and genetic factors that contribute to disease risk. Recent evidence from these models has demonstrated that specific environmental risk factors, such as common infections or gut microbiome dysbiosis, induce immune stress, driving the transformation of preleukemic cells, and harboring genetic alterations, into fully transformed leukemic cells. Such models serve as valuable tools for investigating the mechanisms underlying preleukemic events and can aid in the development of preventive approaches for leukemia in child. Here, we discuss the existing knowledge, learned from mouse models, of the impact of genetic and environmental risk factors on childhood B-ALL evolution and how B-ALL prevention could be reached by interfering with preleukemic cells.

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Oncogene-Induced Reprogramming in Acute Lymphoblastic Leukemia: Towards Targeted Therapy of Leukemia-Initiating Cells

Fregona

Bayet

Gerby

2021

Cancers

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Our understanding of the hierarchical structure of acute leukemia has yet to be fully translated into therapeutic approaches. Indeed, chemotherapy still has to take into account the possibility that leukemia-initiating cells may have a distinct chemosensitivity profile compared to the bulk of the tumor, and therefore are spared by the current treatment, causing the relapse of the disease. Therefore, the identification of the cell-of-origin of leukemia remains a longstanding question and an exciting challenge in cancer research of the last few decades. With a particular focus on acute lymphoblastic leukemia, we present in this review the previous and current concepts exploring the phenotypic, genetic and functional heterogeneity in patients. We also discuss the benefits of using engineered mouse models to explore the early steps of leukemia development and to identify the biological mechanisms driving the emergence of leukemia-initiating cells. Finally, we describe the major prospects for the discovery of new therapeutic strategies that specifically target their aberrant stem cell-like functions.

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Dysregulation of PAX5 causes uncommitted B cell development and tumorigenesis in mice

Cited by 3 publications

References 54 publications

Childhood B-Cell Preleukemia Mouse Modeling

Childhood B-Cell Preleukemia Mouse Modeling

Lessons from mouse models in the impact of risk factors on the genesis of childhood B-cell leukemia

Oncogene-Induced Reprogramming in Acute Lymphoblastic Leukemia: Towards Targeted Therapy of Leukemia-Initiating Cells

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