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Veiga, Diogo F T; Tremblay, Mathieu; Gerby, Bastien; Herblot, Sabine; Haman, André; Gendron, Patrick; Lemieux, Sébastien; Zúñiga-Pflücker, Juan Carlos; Hébert, Josée; Cohen, Joseph Paul; Hoang, Trang
Frontiers in immunology, 03/2022, Letnik: 13Journal Article
Early T-cell development is precisely controlled by E proteins, that indistinguishably include HEB/TCF12 and E2A/TCF3 transcription factors, together with NOTCH1 and pre-T cell receptor (TCR) signalling. Importantly, perturbations of early T-cell regulatory networks are implicated in leukemogenesis. NOTCH1 gain of function mutations invariably lead to T-cell acute lymphoblastic leukemia (T-ALL), whereas inhibition of E proteins accelerates leukemogenesis. Thus, NOTCH1, pre-TCR, E2A and HEB functions are intertwined, but how these pathways contribute individually or synergistically to leukemogenesis remain to be documented. To directly address these questions, we leveraged -deficient mice in which pre-TCR signaling and progression through β-selection is abrogated to dissect and decouple the roles of pre-TCR, NOTCH1, E2A and HEB in SCL/TAL1-induced T-ALL, the use of gain of function transgenic ( ) and or heterozygote mice. As a result, we now provide evidence that both HEB and E2A restrain cell proliferation at the β-selection checkpoint while the clonal expansion of SCL-LMO1-induced pre-leukemic stem cells in T-ALL is uniquely dependent on gene dosage. At the molecular level, HEB protein levels are decreased proteasomal degradation at the leukemic stage, pointing to a reversible loss of function mechanism. Moreover, in -induced T-ALL, loss of one allele is sufficient to bypass pre-TCR signaling which is required for gain of function mutations and for progression to T-ALL. In contrast, monoallelic deletion does not accelerate -induced T-ALL, indicating that and operate in the same pathway. Finally, we identify a tumor suppressor gene set downstream of HEB, exhibiting significantly lower expression levels in pediatric T-ALL compared to B-ALL and brain cancer samples, the three most frequent pediatric cancers. In summary, our results indicate a tumor suppressor function of HEB/TCF12 in T-ALL to mitigate cell proliferation controlled by NOTCH1 in pre-leukemic stem cells and prevent NOTCH1-driven progression to T-ALL.
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