Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia

Front Immunol. 2022 Mar 24;13:867443. doi: 10.3389/fimmu.2022.867443. eCollection 2022.

Abstract

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 Cd3e-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, via the use of Notch1 gain of function transgenic (Notch1IC tg) and Tcf12 +/- or Tcf3 +/- 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 Tcf12 gene dosage. At the molecular level, HEB protein levels are decreased via proteasomal degradation at the leukemic stage, pointing to a reversible loss of function mechanism. Moreover, in SCL-LMO1-induced T-ALL, loss of one Tcf12 allele is sufficient to bypass pre-TCR signaling which is required for Notch1 gain of function mutations and for progression to T-ALL. In contrast, Tcf12 monoallelic deletion does not accelerate Notch1IC-induced T-ALL, indicating that Tcf12 and Notch1 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.

Keywords: E2A/TCF3; HEB/TCF12; LMO1; NOTCH1; SCL/TAL1; T-cell acute lymphoblastic leukemia; tumor suppressor genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Humans
  • Mice
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / genetics
  • Proto-Oncogene Proteins / metabolism
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Receptors, Antigen, T-Cell
  • T-Cell Acute Lymphocytic Leukemia Protein 1
  • T-Lymphocytes / metabolism
  • Transcription Factors / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • NOTCH1 protein, human
  • Proto-Oncogene Proteins
  • Receptor, Notch1
  • Receptors, Antigen, T-Cell
  • T-Cell Acute Lymphocytic Leukemia Protein 1
  • Tcf12 protein, mouse
  • Transcription Factors
  • TCF12 protein, human

Grant support