Early T Cell Differentiation: Lessons from T-Cell Acute Lymphoblastic Leukemia

Abstract : T cells develop from bone marrow-derived self-renewing hematopoietic stem cells (HSC). Upon entering the thymus, these cells undergo progressive commitment and differentiation driven by the thymic stroma and the pre-T cell receptor (pre-TCR). These processes are disrupted in T-cell acute lymphoblastic leukemia (T-ALL). More than 70% of recurring chromosomal rearrangements in T-ALL activate the expression of oncogenic transcription factors, belonging mostly to three families, basic helix-loop-helix (bHLH), homeobox (HOX), and c-MYB. This prevalence is indicative of their importance in the T lineage, and their dominant mechanisms of transformation. For example, bHLH oncoproteins inhibit E2A and HEB, revealing their tumor suppressor function in the thymus. The induction of T-ALL, nonetheless, requires collaboration with constitutive NOTCH1 signaling and the pre-TCR, as well as loss-of-function mutations for CDKN2A and PTEN. Significantly, NOTCH1, the pre-TCR pathway, and E2A/HEB proteins control critical checkpoints and branchpoints in early thymocyte development whereas several oncogenic transcription factors, HOXA9, c-MYB, SCL, and LYL-1 control HSC self-renewal. Together, these genetic lesions alter key regulatory processes in the cell, favoring self-renewal and subvert the normal control of thymocyte homeostasis.
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Chapitre d'ouvrage
Adrian Liston. Development of T Cell Immunity, Academic Press, pp.121 - 156, 2010, <10.1016/S1877-1173(10)92006-1>
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https://hal.archives-ouvertes.fr/hal-00522597
Contributeur : Vincent Delos <>
Soumis le : vendredi 1 octobre 2010 - 10:16:08
Dernière modification le : mercredi 12 octobre 2016 - 01:14:27

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Cédric Tremblay, Thu Hoang, Trang Hoang. Early T Cell Differentiation: Lessons from T-Cell Acute Lymphoblastic Leukemia. Adrian Liston. Development of T Cell Immunity, Academic Press, pp.121 - 156, 2010, <10.1016/S1877-1173(10)92006-1>. <hal-00522597>

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