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Haematologica 2019 Volume 104(8):1608-1616
Acute Lymphoblastic Leukemia
ZEB2 and LMO2 drive immature T-cell lymphoblastic leukemia via distinct oncogenic mechanisms
Steven Goossens,1,2,3 Jueqiong Wang,4 Cedric S. Tremblay,5 Jelle De Medts,6 Sara T’Sas,1,2,3 Thao Nguyen,4 Jesslyn Saw,5 Katharina Haigh,4 David J. Curtis,5 Pieter Van Vlierberghe,1,3 Geert Berx,2,3 Tom Taghon,6 and Jody J. Haigh4,7,8
1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; 2Department for Biomedical Molecular Biology, VIB-UGent Center for Inflammation Research (IRC), Ghent, Belgium; 3Cancer Research Institute Ghent (CRIG), Ghent, Belgium; 4Mammalian Functional Genetics Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia; 5Stem Cell Research Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia; 6Department of Diagnostic Sciences, Ghent University, Ghent, Belgium; 7Department of Pharmacology and Therapeutics, Rady Faulty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada and 8Research Institute in Oncology and Hematology (RIOH),
Cancer Care Manitoba, Winnipeg, Manitoba, Canada
*TT and JJH contributed equally to this work.
ABSTRACT
ZEB1 and ZEB2 are structurally related E-box binding homeobox tran- scription 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 previous- ly demonstrated that Zeb2 also plays pivotal roles in hematopoiesis, con- trolling important cell fate decisions, lineage commitment and fidelity. In addition, upon Zeb2 overexpression, mice spontaneously develop imma- ture 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 signal- ing 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 differenti- ated T-cell precursor cells can also drive malignant T-cell development, sug- gesting 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.
Introduction
T-cell development starts with the migration of bone marrow-derived progenitor cells into the thymus. There, these newly arrived early T-cell progenitors rapidly lose their multipotent character and gradually reprogram into the T-cell lineage. T- cell commitment occurs through an orderly process that is tightly regulated by interplay between key signaling pathways and transcription factors.1 Once com- mitted, immature T-cell progenitors undergo successive and dynamic stages of dif- ferentiation, including positive selection for the T-cell receptor complex in the cor- tex, as well as negative selection for removal of potential self-responsive cells in the medulla.2 Alterations in this process can lead to the development of T-cell acute lymphoblastic leukemia (T-ALL). During malignant transformation, a clonal expan- sion of immature T cells is selected for via the gradual accumulation of advanta- geous epigenetic changes and genetic mutations.3,4
E-proteins, E2A and HEB, play pivotal roles in early T-cell commitment, but also
Correspondence:
STEVEN GOOSSENS
steven.goossens@ugent.be
Received: September 30, 2018. Accepted: January 18, 2019. Pre-published: January 24, 2019.
doi:10.3324/haematol.2018.207837
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