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Diane Krause, MD, PhD

Anthony N. Brady Professor of Laboratory Medicine and Professor of Pathology; Vice Chair for Research Affairs, Laboratory Medicine; Assoc. Director, Yale Stem Cell Center; Assoc. Director, Transfusion Medicine Service; Medical Director, Clinical Cell Processing Laboratory; Medical Director, Advanced Cell Therapy Laboratory

Contact Information

Diane Krause, MD, PhD

Mailing Address

  • Yale Stem Cell Center

    PO Box 208073, 10 Amistad Street

    New Haven, CT 06509

    United States

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 goal of improving therapeutic approaches to hematological diseases including leukemia. We have 2 major foci. 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 the differentiation of pluripotent stem cells to produce function parathyroid epithelial cells in order to develop effective cellular therapy for patients with hypoparathyroidism. We welcome graduate students to join the lab.

Link to laboratory website: https://krauselab.net/

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 can affect Notch signaling; RBM15 represses Notch induced Hes1 promoter activity. In addition, RBM15 is required for m6A RNA modification, and we are studying th role of this epitranscriptomic modification in normal hematopoiesis and leukemogenesis.

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.

Link to laboratory website: https://krauselab.net/

Coauthors

Research Interests

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

Selected Publications