Delineating the mixed lineage leukemia gene expression network in hematopoietic stem cells

Abstract

Hematopoiesis is maintained and sustained throughout life by rare hematopoietic stem cells (HSCs). The hematopoietic system is organized in a hierarchy with the primitive HSCs at the top, generating mature progeny through a series of intermediate and progressively restricted progenitor cells. Normal blood cell development is a tightly controlled process, regulated by transcription factors and epigenetic regulators internally and by cytokines and cellular interactions in the bone marrow microenvironment. Perturbation of the critical molecular regulators is associated often with malignancy of the hematopoietic system, such as leukemia. A key transcriptional regulator in HSCs, the mixed lineage leukemia (MLL) gene, is commonly mutated in both myeloid and lymphoid leukemia (1). MLL is the mammalian ortholog of Drosophila melanogaster Trithorax and widely expressed in multiple organs and tissues including the hematopoietic system and neuronal and vascular systems (2⇓–4). It belongs to a family of histone methyltransferases, where the MLL protein specifically methylates histone H3 on lysine 4 (H3K4), a mark associated with active transcription. MLL is included in a larger multiprotein complex containing protein with chromatin modification and remodeling functions (5). The MLL gene is frequently rearranged through chromosomal translocations, most notably in >70% of cases of infant leukemia and in 10% of all acute myelogeneous leukemia (AML) and acute lymphoblastic leukemia (ALL) (5, 6). The presence of MLL rearrangement in leukemia is generally associated with a poor prognosis. The chromosomal translocations result in MLL fusion proteins that lead to aberrant target gene expression. …