Projects

1. Leukemia is a multigenic disease. We used a transgenic mouse model of T-type acute lymphoblastic leukemia (T-ALL) induced by the oncogene SCL and LMO1 to define the cell of origin of T-ALL and the molecular events that transform normal cells into leukemia-initiating cells. Our recent work defines for the first time a set of additional genetic events that would be sufficient to induce T-ALL in transgenic mice, involving two oncogenic transcription factors, SCL and LMO1, and two important signaling pathways that control the fate of T cells, Notch1 and pre-TCR. Thus, SCL-LMO1 establishes a preleukemic state in thymocytes which with preTCR, facilitates the acquisition of mutations of Notch1. Activated Notch1 converts the pre-leukemic stem cells in leukemia-initiating T cells (Tremblay, Tremblay et al, Genes & Dev, 2010). In addition, our results show that the target cells of oncogenic transformation by these three oncogenes are the progenitors of thymocytes (DN3, DN4) while the more mature thymocytes are more resistant to transformation (Tremblay, Tremblay et al, Genes & Dev, 2010 ). Finally, our observations suggest that the transcription factors E2A-HEB may have a new tumor suppressor function (Herblot et al, Nat Immunol, 2000; work outlined in News & Views, Nat Immunol, 2000; Herblot et al, Mol Cell Biol, 2002, selected by the “Faculty of 1000”).

2. Hematopoietic stem cells (HSCs) normally reside in a protective microenvironment of the bone marrow where they are dormant. These cells divide rarely to meet the production needs of mature hematopoietic cells without compromising the continued retention of a reservoir of HSCs. Our results suggest that SCL/TAL1 preserves the long-term activity of stem cells by maintaining these cells in a quiescent state (Lacombe, Blood, 2010), which could protect them against damage caused by the environment. These results are considered an important advance in our understanding of stem cell biology (Editorial Comment, Blood, 2010).

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