Early T cell differentiation lessons from T-cell acute lymphoblastic leukemia.
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.
Tremblay
Cédric S
CS
Institute of Research in Immunology and Cancer, University of Montreal, Montréal, Québec, Canada.
Hoang
Thu
T
Hoang
Trang
T
D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015513:Oncogene Proteins / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D015513:Oncogene Proteins; D014157:Transcription Factors