The broad interest of the lab is to identify and characterize the mechanisms controlling hematopoietic stem cell (HSC) and progenitor cell function in humans and mice. Current work focuses on the molecular and cellular understanding of HSC fate determination during normal and leukemogenic hematopoiesis.

Molecular basis of hematopoietic stem cell biology
Hematopoietic development is one of the most studied systems of cellular differentiation, beginning with a rare population of multipotent self-renewing HSC giving rise to a hierarchy of progenitor populations with more restricted lineage potential, ultimately leading to the production of all types of mature blood cells. Bone marrow-derived HSC are faced at each cell division with the decision to self-renew, differentiate, migrate, enter senescence, or undergo apoptosis. It has proved difficult to define the complex intrinsic and extrinsic mechanisms that govern the balance of these decisions. We have found that when HSC exit quiescence and enter the cell cycle as a prelude to cell division they temporaly lose efficient in vivo engraftment activity and regulate the expression of particular cell cycle proteins that are associated with specific developmental outcomes (self-renewal vs. differentiation) and developmental fates (myeloid vs. lymphoid). We are now pursuing both genetic and cell biological approaches to further define genes regulating proliferation, differentiation and survival in HSC and progenitor cells. Understanding how such fate decisions are controlled and identifying means to manipulate them has critical implications for human therapy as, every year, more than 45,000 patients undergo bone marrow or peripheral blood progenitor transplantation for treatment of leukemia, lymphoma, immunodeficiency and other diseases.

Leukemia and leukemic stem cells
Leukemias can be viewed as aberrant hematopoietic processes initiated by rare leukemic stem cells (LSC) that have maintained or re-acquired the capacity for indefinite proliferation through accumulated mutations and/or epigenetic changes. A unifying feature of leukemias, and of all cancers, is the capacity for unlimited self-renewal, which is also a defining characteristic of normal HSC. Given these shared attributes, it has been proposed that leukemias may be initiated by transforming events taking place in HSC. Alternatively, leukemias may arise from more committed progenitors due to mutations, epigenetic changes and/or selective gene expression that enhance their otherwise limited self-renewal capabilities. Identifying the developmental origin of the LSC for each type of leukemia is a critical step in understanding their respective biology and in providing powerful diagnostic, prognostic and therapeutic tools in the clinic. Yet, despite their obvious importance, much remains to be learned about the nature of LSC and the mechanisms responsible for their emergence in the course of the disease. Thus, a major focus of the lab is to use mouse models of human leukemias to identify their LSC, elucidate the molecular mechanisms involved in their leukemic transformation, and test their relevance for human disease. We have found that the AP-1 transcription factor JunB is a negative regulator of HSC function, that loss of JunB at the stem cell level leads to a myeloproliferative disorder (MPD) similar to human chronic myelogenous leukemia (CML), and that cells of the HSC phenotype are the only LSC for this mouse model of human leukemia. Future studies will be aimed at dissecting the molecular events involved in the transformation of JunB-deficient HSC into LSC entity.

Passegué E.*, Wagers A.J.*, Guiriato S., Anderson W., Weissman, I.L. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J. Exp. Med. 2005: 202; 1599-611.

Jamieson C.H.M., Weissman I.L., Passegué E. Chronic versus acute myelogenous leukemia: A question of self-renewal. Cancer Cell 2004: 6; 531-3.

Passegué E., Wagner E.F., Weissman I.L. JunB-deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 2004: 119; 431-43.

Cozzio A.*, Passegué E.*, Ayton P.*, Karsunky H., Cleary M.L., Weissman I.L. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes & Dev. 2003: 17; 3029-35.

Passegué E., Jamieson C.H.M., Ailles L.E., Weissman I.L. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? PNAS 2003: 100 (Suppl. 1); 11842-9.

Passegué E.*, Jochum W.*, Schorpp-Kistner M., Möhle-Steinlein U., Wagner E.F. Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking JunB expression in the myeloid lineage. Cell 2001: 104; 21-32.

*Authors Contributed Equally