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Stage-specific roles for Zmiz1 in Notch-dependent steps of early T-cell development

Qing Wang, Ran Yan, Nancy Pinnell, Anna C. McCarter, Yeonjoo Oh, Yiran Liu, Cher Sha, Noah F. Garber, Yitong Chen, Qingqing Wu, Chia-Jui Ku, Ivy Tran, Amparo Serna Alarcon, Rork Kuick, James Douglas Engel, Ivan Maillard, Tomasz Cierpicki and Mark Y. Chiang

Key points

  • The Notch1 cofactor Zmiz1 induces a subset of Notch target genes and drives pre-T cell proliferation during normal and stress thymopoiesis.

  • Disrupting the Zmiz1-Notch1 protein-protein interaction impairs Myc induction, pre-T cell expansion and leukemic proliferation.

Abstract

Notch1 signaling must elevate to high levels in order to drive the proliferation of CD4-CD8- double-negative (DN) thymocytes and progression to the CD4+CD8+ double-positive (DP) stage through beta-selection. During this critical phase of pre-T cell development, which is also known as the DN-DP transition, it is unclear whether the Notch1 transcriptional complex strengthens its signal output as a discrete unit or through cofactors. We previously showed that the protein inhibitor of activated STAT (PIAS)-like coactivator Zmiz1 is a context-dependent cofactor of Notch1 in T-cell leukemia. We also showed that withdrawal of Zmiz1 generated an early T-lineage progenitor (ETP) defect. Here, we show that this early defect seems inconsistent with loss-of-Notch1 function. In contrast, at the later pre-T cell stage, withdrawal of Zmiz1 impaired the DN-DP transition by inhibiting proliferation, like withdrawal of Notch. In pre-T cells, but not ETPs, Zmiz1 cooperatively regulated Notch1 target genes Hes1, Lef1, and Myc. Enforced expression of either activated Notch1 or Myc partially rescued the Zmiz1-deficient DN-DP defect. We identified residues in the tetratricopeptide repeat (TPR) domain of Zmiz1 that bind Notch1. Mutating only a single residue impaired the Zmiz1-Notch1 interaction, Myc induction, the DN-DP transition, and leukemic proliferation. Similar effects were seen using a dominant-negative TPR protein. Our studies identify stage-specific roles of Zmiz1. Zmiz1 is a context-specific cofactor for Notch1 during Notch/Myc-dependent thymocyte proliferation, whether normal or malignant. Finally, we highlight a vulnerability in leukemic cells that originated from a developmentally important Zmiz1-Notch1 interaction that is hijacked during transformation from normal pre-T cells.

  • Submitted February 26, 2018.
  • Accepted July 29, 2018.