title: Somatic inactivation of ATM in hematopoietic cells predisposes mice to cyclin D3 dependent T cell acute lymphoblastic leukemia.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of immature T cells that exhibits heterogeneity of oncogenic lesions, providing an obstacle for development of more effective and less toxic therapies. Inherited deficiency of ATM, a regulator of the cellular DNA damage response, predisposes young humans and mice to T-ALLs with clonal chromosome translocations. While acquired ATM mutation or deletion occurs in pediatric T-ALLs, the role of somatic ATM alterations in T-ALL pathogenesis remains unknown. We demonstrate here that somatic Atm inactivation in haematopoietic cells starting as these cells differentiate in utero predisposes mice to T-ALL at similar young ages and harboring analogous translocations as germline Atm-deficient mice. However, some T-ALLs from haematopoietic cell specific deletion of Atm were of more mature thymocytes, revealing that the developmental timing and celluar origin of Atm inactivation influences the phenotype of ATM-deficient T-ALLs. Although it has been hypothesized that ATM suppresses cancer by preventing deletion and inactivation of TP53, we find that Atm inhibits T-ALL independent of Tp53 deletion. Finally, we demonstrate that the Cyclin D3 protein that drives immature T cell proliferation is essential for transformation of Atm-deficient thymocytes. Our study establishes a pre-clinical model for pediatric T-ALLs with acquired ATM inactivation and identifies the cell cycle machinery as a therapeutic target for this aggressive childhood T-ALL subtype.
authors: a Division of Oncology, Department of Pediatrics ; Children's Hospital of Philadelphia ; Philadelphia , PA USA.
authors: Lori A
authors: LA
authors: Ehrlich
authors: Katherine
authors: K
authors: Yang-Iott
authors: Amy
authors: A
authors: DeMicco
authors: Craig H
authors: CH
authors: Bassing
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D056743:Cyclin D3 / Q000378:metabolism*; D004198:Disease Susceptibility; D017353:Gene Deletion; D020868:Gene Silencing; D042822:Genomic Instability; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006579:Heterozygote; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology*; D060168:Thymocytes / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D056743:Cyclin D3; D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse
keywords: ATM; Cyclin D3; T-cell acute lymphoblastic leukemia; translocations; tumor suppression