ZEB2 and LMO2 drive immature T-cell lymphoblastic leukemia via distinct oncogenic mechanisms

Steven Goossens, Jueqiong Wang, Cedric S. Tremblay, Jelle De Medts, Sara T'sas, Thao Nguyen, Jesslyn Saw, Katharina Haigh, David J. Curtis, Pieter Van Vlierberghe, Geert Berx, Tom Taghon, Jody J. Haigh

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

ZEB1 and ZEB2 are structurally related E-box binding homeobox transcription factors that induce epithelial to mesenchymal transitions during development and disease. As such, they regulate cancer cell invasion, dissemination and metastasis of solid tumors. In addition, their expression is associated with the gain of cancer stem cell properties and resistance to therapy. Using conditional loss-of-function mice, we previously demonstrated that Zeb2 also plays pivotal roles in hematopoiesis, controlling important cell fate decisions, lineage commitment and fidelity. In addition, upon Zeb2 overexpression, mice spontaneously develop immature T-cell lymphoblastic leukemia. Here we show that pre-leukemic Zeb2-overexpressing thymocytes are characterized by a differentiation delay at beta-selection due to aberrant activation of the interleukin-7 receptor signalling pathway. Notably, and in contrast to Lmo2-overexpressing thymocytes, these pre-leukemic Zeb2-overexpressing T-cell progenitors display no acquired self-renewal properties. Finally, Zeb2 activation in more differentiated T-cell precursor cells can also drive malignant T-cell development, suggesting that the early T-cell differentiation delay is not essential for Zeb2-mediated leukemic transformation. Altogether, our data suggest that Zeb2 and Lmo2 drive malignant transformation of immature T-cell progenitors via distinct molecular mechanisms.

Original languageEnglish
Pages (from-to)1608-1616
Number of pages9
JournalHaematologica
Volume104
Issue number8
DOIs
Publication statusPublished - 31 Jul 2019

Cite this