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Hematopoiesis and Leukemogenesis Using Bone Marrow Derived Stem and Progenitor Cells

Most projects in the Krause lab focus on molecular mechanisms that regulate early hematopoiesis and may contribute to leukemogenesis when regulation fails. Specifically, we use primary cells as well as murine and human embryonic stem cells to study RBM15 and MKL1, two genes that are fused in the t(1;22) translocation associated with Acute Megakaryoblastic Leukemia AMKL). We are studying the roles of RBM15 and MKL1 in normal hematopoiesis and leukemogenesis.

We have shown that RBM15 is downregulated as blood stem cells differentiate such that megakaryoblasts express low levels of RBM15. When RBM15 is overexpressed, it prevents myeloid differentiation, and when RBM15 is inhibited or deleted, myeloid differentiation is enhanced, and there is a loss of hematopoietic stem and progenitor cells. RBM15 is a member of the spen family of proteins that share a C-terminal SPOC domain that bind to the nuclear corepressor complex. We have shown that RBM15 represses Notch induced Hes1 promoter activity. Also, RBM15, which is an RNA binding protein, plays a role in post-transcriptional changes to RNA icnluding splicing and methylation. Thus, RBM15 plays a role in hematopoiesis by maintaining myeloid cells in an undifferentiated state, and this activity is potentially mediated by regulation of Notch signaling and/or RNA processing.

MKL1, also part of the t(1;22) translocation specific to acute megakaryoblastic leukemia, is activates the transcription factor serum response factor (SRF). The Krause laboratory has shown that MKL1 expression is upregulated during megakaryocytic differentiation, and that overexpression of MKL1 enhances megakaryocytic differentiation. The effect of MKL1 is abrogated when SRF is knocked down, suggesting that MKL1 acts through SRF. Knock out of MKL1 in mice leads to reduced platelet counts, and reduced ploidy in bone marrow megakaryocytes. Thus, MKL1 promotes physiological maturation of human and murine megakaryocytes.

Ongoing work on RBM15 is focused on the mechanisms by which it affects notch signaling, its RNA binding properties, ands its ability to bind to other nuclear proteins to affect transcription. Ongoing work on MKL1 is focused on the mechanisms by which MKL1 promotes megakaryocytopoiesis.