Experimental Hematology and Cancer Biology

Marie-Dominique Filippi, PhD

Title

Research Assistant Professor

Email

Marie-Dominique.Filippi@cchmc.org

Phone

513-636-0991

Fax

513-636-3768

Credentials

PharmD: University of Rene Descartes, Paris, France, 1998
Residency: Hematopathology, University of Rene Descartes, Assistance public Hospital of Paris, Paris, France.
Certification: Hematopathology, 2001
PhD: University of Denis Diderot, Paris, France, 2001

Awards and Honors

ASH Scholar Award: July 2005-June 2007

PhD with Suma Cum Laude

Research

I am particularly interested in dissecting the molecular mechanism of hematopoietic cell migration, including neutrophils and hematopoietic stem cells in physiological settings. Migration is a critical function of hematopoietic cell in which actin cytoskeleton reorganization plays a central role. Because hematopoietic cells are utilized for the therapy of multiple blood diseases and neutrophils are responsible for maintaining an immunocompetence status, understanding the molecular mechanism of normal hematopoietic cell functions is of potential therapeutic importance. The small RHO GTPase family, members of the Ras superfamily, including Rac, RHO and CDC42, play key roles in regulating many of these functions. During my post-doc in the laboratory of Dr David Williams, we have demonstrated that two highly related proteins, Rac1 and Rac2, of the small Rho GTPase family, have distinct functions in the control of hematopoietic cell functions. In particular in neutrophils, we have shown that both Rac1 and Rac2 regulate cell migration but with distinct mechanism (Gu and Filippi et al, Science 2003) both in vitro and in vivo. In addition to this work, we have dissected the sequence/determinant specificity of Rac2 versus Rac1 functions in neutrophils and demonstrated that Rac2 controls its functions, at least in part, by distinct subcellular distributions of these GTPases (Tao et al, Blood 2002, Filippi et al, Nat Immunol 2004), highlighting one important mechanism controlling cellular functions.

My laboratory, in collaboration with Dr David Williams and Dr Yi Zheng, is now focused on determining the role of CDC42 and RhoA in neutrophil migration and in determining specifically the role of RhoA in hematopoietic stem cell migration and proliferation using gene targeted knock out mice for CDC42 and RhoA and their respective regulator CDC42GAP and 190RhoGAP. These studies will use in vitro and in vivo assays of cell migration as well as immunofluorescence microscopy to study cytoskeleton rearrangement associated with cell migration.

The long term goal of these studies is to identify new molecular targets of potential therapeutic importance.

Research Grants and Contracts

Trustee Award, Cincinnati Children's Research Foundation 2004-2006

ASH scholar Award 2005-2007

Publications, Most Recent

Connect to Marie-Dominique Filippi's publications on PubMed

Carstanjen D, Yamauchi A, Koornneef A, Zang H, Filippi MD, Harris C, Towe J, Atkinson S, Zheng Y, Dinauer MC, Williams DA. Rac2 regulates neutrophil chemotaxis, superoxide production, and myeloid colony formation through multiple distinct effector pathways. J Immunol. 2005 Apr 15;174(8):4613-20.

Filippi MD, Harris CE, Meller J, Gu Y, Zheng Y, Williams DA. Localization of Rac2 via the C terminus and aspartic acid 150 specifies superoxide generation, actin polarity and chemotaxis in neutrophils.Nat Immunol. 2004 Jul;5(7):744-51.

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.

Presentations, Most Recent

46th Annual meeting of American Society of Hematology, San Diego (USA), December 4-7, 2004.
"The Rho GTPase CDC42 regulator CDC42GAP plays a critical role in neutrophil migration via podosome-like formation." M-D Filippi, H Xu, J Towe, C E Harris, K Szczur, S Atkinson, Y Zheng, D A Williams. Oral presentation

33rd Annual meeting of the International Society for Experimental Hematology (ISEH), New Orleans (USA), July 17-20 2004. International meeting
"Rho GTPases of the Rac family are central regulators of hematopoietic-derived inflammatory processes." M-D Filippi, P-Y Berclaz, C Harris, K Szczur, B Trapnell, D Williams. Poster presentation

45th Annual meeting of American Society of Hematology, San Diego (USA), December 5-9, 2003.
"Unique intracellular localization of Rac2 specifies superoxide generation, actin polarization and chemotaxis in primary neutrophils." M-D. Filippi, C.E.Harris, J. Meller, Y. Gu, Y. Zheng, D.A. Williams. Oral presentation

"The Ras-related Rho GTPases, Rac1 and Rac2, regulate the homing, engraftment and mobilization of hematopoietic stem cells and progenitor cells." J.A. Cancelas, Y. Gu, M-D. Filippi, R. Prabhakar, A.W. Lee, J.E. Siefring, D.A. Williams. Oral presentation

32nd Annual meeting of the International Society for Experimental Hematology (ISEH), Paris (France), July 5-8 2003.
"Sequence determinants of Rac2 specificity in regulating actin assembly and neutrophil chemotaxis." M-D. Filippi, C.E.Harris, J. Meller, Y. Zheng, D.A. Williams. Poster presentation

First Annual Midwest Blood Club Symposium, Cincinnati (USA), April 12-13, 2003.
"Sequence determinants of Rac2 specificity in regulating actin assembly and neutrophil chemotaxis." M-D. Filippi, C.E.Harris, J. Meller, Y. Zheng, D.A. Williams. Poster presentation

44th Annual meeting of American Society of Hematology, Philadelphia (USA), December 6-10, 2002.
"Rac1 and Rac2 play both overlapping and non-redundant roles in control of neutrophil functions." M-D. Filippi, Y. Gu, E.P. Williams, C.E. Harris, A. Ayele, S. Atkinson, D.J. Kwiatkowski, D.A. Williams. Oral presentation

"The highly related Rho GTPases, Rac1 and Rac2, separately control hematopoietic stem cell survival and cycle progression, but together regulate the engraftment phenotype." Y. Gu. M-D. Filippi, J.A. Cancelas, J.E. Siefring, E.P. Williams, A. Jasti, R, Prabhakar, D.J. Kwiatkowski, D.A. Williams. Oral presentation

31st Annual meeting of the International Society for Experimental Hematology (ISEH), Montreal (Canada), July 5-9 2002.
"The polybasic motif of the RhoGTPase Rac2, located in the C-terminus domain, is responsible for the specific function of Rac2 in superoxide production but not in chemotaxis." M-D. Filippi, A. Yamouch. Y. Gu, A. Ayele, M. Dinauer, D.A. Williams. Oral presentation