期刊
GENES & DEVELOPMENT
卷 24, 期 11, 页码 1093-1105出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1897910
关键词
T-ALL; Notch1; SCL/TAL1; LMO1; leukemia-initiating cell; pre-TCR
资金
- Canadian Cancer Society Research Institute
- Canada Research Chair program
- Fonds de Recherche en Sante du Quebec (FRSQ)
- Cole Foundation
- Canadian Institute for Health Research (CIHR)
- Leukemia Research Fund of Canada
- Terry Fox Foundation [700153]
- NATIONAL CANCER INSTITUTE [ZIABC010982, ZIASC010378] Funding Source: NIH RePORTER
Deciphering molecular events required for full transformation of normal cells into cancer cells remains a challenge. In T-cell acute lymphoblastic leukemia (T-ALL), the genes encoding the TAL1/SCL and LMO1/2 transcription factors are recurring targets of chromosomal translocations, whereas NOTCH1 is activated in >50% of samples. Here we show that the SCL and LMO1 oncogenes collaborate to expand primitive thymocyte progenitors and inhibit later stages of differentiation. Together with pre-T-cell antigen receptor (pre-TCR) signaling, these oncogenes provide a favorable context for the acquisition of activating Notch1 mutations and the emergence of self-renewing leukemia-initiating cells in T-ALL. All tumor cells harness identical and specific Notch1 mutations and Tcr beta clonal signature, indicative of clonal dominance and concurring with the observation that Notch1 gain of function confers a selective advantage to SCL-LMO1 transgenic thymocytes. Accordingly, a hyperactive Notch1 allele accelerates leukemia onset induced by SCL-LMO1 and bypasses the requirement for pre-TCR signaling. Finally, the time to leukemia induced by the three transgenes corresponds to the time required for clonal expansion from a single leukemic stem cell, suggesting that SCL, LMO1, and Notch1 gain of function, together with an active pre-TCR, might represent the minimum set of complementing events for the transformation of susceptible thymocytes.
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