Diane Krause, MD, PhD

Professor of Laboratory Medicine, of Cell Biology and of Pathology; Assoc. Director, Yale Stem Cell Center; Assoc. Director, Transfusion Medicine Service; Medical Director, Clinical Cell Processing Laboratory; Medical Director, Advanced Cell Therapy Laboratory

Research Departments & Organizations

Laboratory Medicine: Blood Bank | Krause Lab

Cell Biology: Cytoskeletal Dynamics | Developmental Cell Biology and Genetics

Pathology

Embryonic Stem Cell Research Oversight

Vascular Biology and Therapeutics Program

WHRY Pilot Project Program Investigators

Yale Cancer Center: Genomics, Genetics, and Epigenetics

Yale Stem Cell Center

Office of Cooperative Research

Research Interests

Bone Marrow Transplantation; Cell Biology; Gene Expression; Hematology; Leukemia; Medical Laboratory Science; Pathology; Stem Cells

Research Summary

The overall goals of my research are to characterize bone marrow (BM) derived stem/progenitor cells, and to define the mechanisms that regulate the self-renewal and differentiation of these cells with the hopes that the findings can be translated to improved therapeutics. We have 2 major foci, and we welcome graduate students to join the lab. The first is the molecular mechanism(s) regulating gene expression during normal and malignant hematopoiesis. We are using hematopoietic stem cells and human embryonic stem cells to better understand Acute Megakaryoblastic Leukemia. In vitro and in vivo cell and molecular approaches will help us to better understand hematopoiesis and leukemogenesis. The second focus is based on our discovery that BM cells can differentiate into mature epithelial cells of the lung, liver, GI tract and skin. Projects are ongoing on the functional effects of BM transplantation and to determine the cells and mechanisms responsible for this engraftment.

Specialized Terms: Bone Marrow Transplantation; Stem Cells; Cell and Molecular Hematology; Leukemia

Extensive Research Description

Hematopoiesis and leukemogenesis using bone marrow derived stem and progenitor cells Projects in the lab focus on molecular mechanisms that regulate early hematopoiesis and may be dysfunctional in leukemogenesis. Specifically, we are using 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 myelopoiesis and leukemogenesis. We have shown that RBM15 is downregulated as hematopoietic stem cells differentiate down the myeloid lineage 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 cell self-renewal. RBM15 is a member of the spen family of proteins that share a C-terminal SPOC domain that bind to the nuclear corepressor complex. Consistent with other members of the SPOC domain family that can affect Notch signaling, we have shown that RBM15 represses Notch induced Hes1 promoter activity. RBM15 coimmunoprecipitates with RBPJk, a critical transcription factor in the Notch signaling pathway. Thus, RBM15 plays a role in hematopoiesis by maintaining myeloid cells in an undifferentiated state, and this activity is mediated by inhibition of Notch signaling.

MKL1, identified at the C-terminus of the t(1;22) translocation specific to acute megakaryoblastic leukemia, is highly expressed in differentiated muscle cells and promotes muscle differentiation by activating serum response factor (SRF). The Krause laboratory has shown that MKL1 expression is upregulated during murine and human megakaryocytic differentiation, and that enforced overexpression of MKL1 enhances megakaryocytic differentiation. When the Human Erythroleukemia (HEL) cell line is induced to differentiate with TPA, overexpression of MKL1 results in an increased number of megakaryocytes with a concurrent increase in ploidy. MKL1 overexpression also promotes thrombopoietin-induced megakaryocytic differentiation of primary human CD34+ cells. The effect of MKL1 is abrogated when SRF is knocked down, suggesting that MKL1 acts through SRF. Consistent with these findings in human cells, 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.

Clinical Trials

Conditions Study Title
Diseases of the Blood Apheresis for Collection of Peripheral Blood Mononuclear Cells (PBMC) for Clinical and Basic Science Research
Melanoma, skin A Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Melanoma

Selected Publications

See list of PubMed publications

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