DF/HCC Program Affiliation

Cancer Cell Biology
Leukemia

DF/HCC Associations

Member, Center Scientific Council
Institutional Representative for CHB, Executive Committee

Research Abstract

Primary Research Interest

The major interest of our laboratory is focused on the biology of hematopoietic stem cells. The work has focused on understanding the interaction of hematopoietic stem cells with the bone marrow and abnormalities of these interactions which are associated with leukemia. These basic studies contribute to our translational research focus that utilizes hematopoietic stem cells as a target for gene therapy manipulations.

Projects

Rho GTPases in normal hematopoiesis

The Rho family of small GTPases are members of the Ras superfamily. The best studied members of this family are Rac1, RhoA and Cdc42. In fibroblasts, Rho activation induces the assembly of filamentous (F)-actin and myosin filaments (stress fibers), while Rac and Cdc42 promote the formation of surface protrusions and ruffling (lamellipodia) and finger-like membrane extensions (filopodia) respectively, both actin containing structures. Using gene-targeted mice, we have shown that Rac plays a critical role in blood cell development and function. Rac activity has been demonstrated to be important for such diverse functions as retention in the bone marrow, long-term engraftment of hematopoietic stem cells and hematopoietic stem cell mobilization. Furthermore, in more committed hematopoietic cells Rac activity is associated with B–lymphocyte development and signaling, granulocyte chemotaxis and superoxide production, migration and degranulation of mast cells, and maturation of TRAP–positive, pro-osteoclasts into multi-nucleated osteoclasts.

Rho GTPases in leukemia

Activation of Rac has previously been shown in Bcr-abl+ chronic myelogenous leukemia (CML). We have utilized gene-targeted mice lacking Rac GTPases to show that Rac is critical for the development and evolution of the myeloproliferative disease associated with expression of the p210 Bcr-abl oncogene. These studies have led to the testing of a small molecule inhibitor of Rac developed by our colleague, Dr. Yi Zheng, on primary CML samples and in the mouse model. These studies are being done in collaboration with Dr. Jose Cancelas, Dr. Brian Druker and Dr. John Byrd. We are also studying the potential role of other GTPases in acute myeloid leukemia and chronic. These studies examine primary samples and leukemia cell lines and are specifically examining the role of Rac and another GTPase, called RhoH, in the leukemia cell phenotype. This work is being done in collaboration with Drs. Yi Gu and John Byrd.

Publications

• Chae HD, Lee KE, Williams DA, Gu Y.Cross-talk between RhoH and Rac1 in regulation of actin cytoskeleton and chemotaxis of hematopoietic progenitor cells.Blood 2007 Dec 18.
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• Thomas EK, Cancelas JA, Chae HD, Cox AD, Keller PJ, Perrotti D, Neviani P, Druker BJ, Setchell KD, Zheng Y, Harris CE, Williams DA.Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative dis
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• Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA.RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development.Nat Immunol 2006 Nov;7(11):1182-90.
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• Cancelas JA, Williams DA.Stem cell mobilization by beta2-agonists.Nat Med 2006 Mar;12(3):278-9.
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• Yamada Y, Rothenberg ME, Lee AW, Akei HS, Brandt EB, Williams DA, Cancelas JA.The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease.Blood 2006 May 15;107(10):4
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• Schambach A, Bohne J, Chandra S, Will E, Margison GP, Williams DA, Baum C.Equal potency of gammaretroviral and lentiviral SIN vectors for expression of O6-methylguanine-DNA methyltransferase in hematopoietic cells.Mol Ther 2006 Feb;13(2):391-400.
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• Wang L, Yang L, Filippi MD, Williams DA, Zheng Y.Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment.Blood 2006 Jan 1;107(1):98-105.
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• Cancelas JA, Lee AW, Prabhakar R, Stringer KF, Zheng Y, Williams DA.Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization.Nat Med 2005 Aug;11(8):886-91.
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• Gu Y, Filippi MD, Cancelas JA, Siefring JE, Williams EP, Jasti AC, Harris CE, Lee AW, Prabhakar R, Atkinson SJ, Kwiatkowski DJ, Williams DA.Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases.Science 2003 Oct 17;302(5644):445-9.
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