The Roles of Pten in Hematopoietic Stem Cell Regulation and Leukemogenesis.

Pten was the first phosphatase identified as a tumor suppressor and one of the most frequently mutated genes involved in human tumor/cancer. Pten, involved in regulation of both PI3K/Akt and MEK/Erk activity, is downstream of growth factor, cytokine, integrin and cadherin signaling pathways and therefore plays important roles in cell growth, survival, differentiation, metabolism and migration. Although Pten mutation is not common in leukemic cells, phosphorylated Pten (p-Pten), which represents the inactive form of Pten, has been observed in a majority of acute myeloid leukemias that are associated with poor clinical outcomes. To explore the role of Pten in hematopoietic stem cell (HSC) regulation and leukemogenesis, we generated an interferon-inducible Pten knockout mouse by crossing Mx1Cre mice with Pten^loxp mice. All of the mutant mice developed myeloproliferative disorder characterized by increased peripheral white blood cell counts, hyperproliferative macrophages and granulocytes in bone marrow and spleen, and multiple tissue infiltration by myeloid cells. The HSC number was decreased in the bone marrow but mobilized and expanded in the spleen. Extra-medullar hematopoiesis was shown by dramatically increased myeloid and erythroid progenitors in the spleen. B lymphocyte differentiation was blocked at the common lymphoid progenitor stage, while the T cell number was increased in all hematopoietic tissues. Compared to wild type, Pten mutant HSCs and progenitor cells were highly proliferative, forming larger colonies in an in vitro culture study. However, Pten mutant HSCs showed reduced competency in repopulation assay after in vivo bone marrow transplantation. Our study demonstrates that Pten plays important roles in restricting HSC activation, proliferation and mobilization. Pten also plays a role in HSC lineage decision by favoring myeloid differentiation at the expense of B lymphocyte lineage.