Defining MLLT3 regulated molecular pathways in hematopoietic stem cell self-renewal
University of California, Los Angeles
Molecular, Cell, & Developmental Biology
Hematopoietic stem cells (HSCs) are multipotent blood cells that can self-renew and reconstitute the entire hematopoietic system when transplanted into an irradiated recipient. As such, HSC transplantation has been used to cure congenital and acquired hematopoietic diseases. Limited availability of HLA-matched HSCs, however, restricts the number of patients who can benefit from HSC transplantation therapies. To this end, pluripotent stem cells such as human embryonic stem cells (hESC) are potential unlimited sources of HSCs that can bypass the problem of HLA-matching and graft-versus-host disease. Currently, hESC-derived hematopoietic stem and progenitor cells (HSPC) acquire the HSC surface phenotype (CD34+CD38-CD90+GPI80+/-), but lack self-renewal potential and are largely restricted to myeloid and erythroid lineages. Microarray analysis comparing CD34+CD38-CD90+GPI80+ human fetal liver HSCs (FL-HSCs) and CD34+CD38-CD90+GPI80- hESC-derived HSPCs identify the gene MLLT3 to be highly expressed in FL-HSCs while downregulated in hESC-derived HSPCs. Furthermore, MLLT3 is highly expressed in HSCs of many stages of development, such as cord blood and the bone marrow. Lentiviral overexpression of MLLT3 in FL-HSCs prolongs the maintenance of the self-renewing HSC population over time, while shRNA knockdown of MLLT3 in FL-HSCs diminishes the self-renewing population. Together, the data indicates that MLLT3 is a candidate transcriptional regulator that promotes HSC self-renewal. It is of prime interest to uncover the specific binding targets of MLLT3 to characterize how it regulates the expression of downstream genes to coordinate HSC self-renewal. Understanding the mechanisms of MLLT3 will help define the conditions required to generate HSCs in culture for therapeutic use.