Michelle Le Beau, Ph.D.

APPOINTMENTS

  • Arthur and Marian Edelstein Professor, Department of Medicine - Section of Hematology/Oncology, Department of Human Genetics, Ben May Department for Cancer Research, Committee on Cancer Biology, Committee on Genetics
  • Director, The University of Chicago Comprehensive Cancer Center (UCCCC)
  • Director, Cancer Cytogenetics Laboratory

EDUCATION

Ph.D., University of Illinois-Chicago, 1981

M.S., University of Illinois-Chicago, 1978

B.S., Purdue University, 1976

CONTACT INFORMATION

The University of Chicago
AMB H212Q, (MC 1140)
5841 South Maryland Avenue
Chicago, Illinois 60637

mlebeau@medicine.bsd.uchicago.edu

Phone:  (773) 702-0795

Website (Cancer Research Center)

Website (Ben May)

RESEARCH SUMMARY

Molecular Analysis of Recurring Chromosomal Abnormalities in Human Tumors; Identification of Cooperating Mutations and Genetic Pathways Leading to Transformation

Human tumors are characterized by recurring chromosomal abnormalities as well as molecular changes that lead to the activation of oncogenes, and loss of function of tumor suppressor genes.  Dr. Le Beau has been recognized for her work in identifying recurring cytogenetic abnormalities, in defining the clinical, morphological, and cytogenetic subsets of leukemia, in identifying the genetic pathways that lead to myeloid leukemias, and on the application of fluorescence in situ hybridization technology for clinical diagnostics and gene mapping.

Much of her work has focused on characterizing the cytogenetic, clinical, and morphologic features of therapy-related myeloid neoplasms (t-MN), an aggressive form of myelodysplastic syndrome or acute myeloid leukemia arising in patients who have been treated with cytotoxic therapy for a primary malignant disease, such as a solid tumor.  The contributions of the Le Beau laboratory include: 1) the recognition that abnormalities of chromosomes 5 and/or 7 are the hallmark of t-MN following alkylating agent therapy; 2) delineation of a 970 kb commonly deleted segment (CDS) of 5q, and preparation of a genomic contig and transcript map of this region; 3) determining that the myeloid leukemia gene acts by haploinsufficiency and proposing that t-MN associated with a del(5q) results from the simultaneous loss of multiple haploinsufficient genes on 5q; 4) identifying the first haploinsufficient myeloid leukemia suppressor gene within the CDS of 5q, EGR1; 5) determining that APC (5q22.2) is haploinsufficient in myeloid neoplasms with a del(5q), that Apc is essential for the maintenance and survival of hematopoietic stem and progenitor cells in mice, and that haploinsufficiency results in a fatal macrocytic anemia, recapitulating characteristic features of t-MN with a del(5q); 6) demonstrating that haploinsufficiency of Egr1 and Apc cooperate to accelerate anemia onset; and 7) determining that loss of Tp53 in BM cells haploinsufficient for both Egr1 and Apc is permissive for the development of AML in mice, thereby establishing the first mouse model for t-MN with a del(5q).  Ongoing projects include the delineation of additional genes on chromosome 5 that cooperate with EGR1 and APC in the pathogenesis of t-MN, as well as the analysis of the synergistic cross-talk between the bone marrow microenvironment or “stem cell niche” and hematopoietic stem cells during normal blood cell development and in leukemogenesis. 

SELECTED PAPERS

Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice. Stoddart A, Fernald AA, Wang J, Davis EM, Karrison T, Anastasi J, Le Beau MM (2014 Feb) Blood. 2014 Feb 13;123(7):1069-78. doi: 10.1182/blood-2013-07-517953. Epub 2013 Dec 31. 24381225 ( Full Text )

Cell intrinsic and extrinsic factors synergize in mice with haploinsufficiency for Tp53, and two human del(5q) genes, Egr1 and Apc. Stoddart A, Wang J, Fernald AA, Karrison T, Anastasi J, Le Beau MM (2014 Jan) Blood. 2014 Jan 9;123(2):228-38. doi: 10.1182/blood-2013-05-506568. Epub 2013 Nov 21. 24264229 ( Full Text )

beta-Catenin induces T-cell transformation by promoting genomic instability. Dose M, Emmanuel AO, Chaumeil J, Zhang J, Sun T, Germar K, Aghajani K, Davis EM, Keerthivasan S, Bredemeyer AL, Sleckman BP, Rosen ST, Skok JA, Le Beau MM, Georgopoulos K, Gounari F (2014 Jan) Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):391-6. doi: 10.1073/pnas.1315752111. Epub 2013 Dec 26. 24371308 ( Full Text )

MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Chen C, Liu Y, Rappaport AR, Kitzing T, Schultz N, Zhao Z, Shroff AS, Dickins RA, Vakoc CR, Bradner JE, Stock W, Le Beau MM, Shannon KM, Kogan S, Zuber J, Lowe SW. (2014 May) Cancer Cell. 2014 May 12;25(5):652-65. doi: 10.1016/j.ccr.2014.03.016. Epub 2014 May 1.

CUX1 is a haploinsufficient tumor suppressor genes on chromosome 7 frequently inactivated in acute myeloid leukemia. McNerney ME, Brown CD, Wang X, Bartom ET, Karmakar S, Bandlamudi C, Yu S, Ko J, Sandall BP, Stricker T, Anastasi J, Grossman RL, Cunningham JM, Le Beau MM, White KP. (2013 Feb) Blood. 2013 Feb 7;121(6):975-83. doi: 10.1182/blood-2012-04-426965. Epub 2012 Dec 3. 3567344

Dominant role of oncogene dosage and absence of tumor suppressor activity in Nras-driven hematopoietic transformation. Xu J, Haigis KM, Firestone AJ, McNerney ME, Li Q, Davis E, Chen SC, Nakitandwe J, Downing J, Jacks T, Le Beau MM, Shannon K (2013 Sep) Cancer Discov. 2013 Sep;3(9):993-1001. doi: 10.1158/2159-8290.CD-13-0096. Epub 2013 Jun 3. 23733505 ( Full Text )

Revised international prognostic scoring system for myelodysplastic syndromes. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstocker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D (2012 Sep) Blood. 2012 Sep 20;120(12):2454-65. Epub 2012 Jun 27. 22740453

Haploinsufficiency of Apc leads to ineffective hematopoiesis. Wang J, Fernald AA, Anastasi J, Le Beau MM, Qian Z (2010 Apr) Blood. 2010 Apr 29;115(17):3481-8. doi: 10.1182/blood-2009-11-251835. Epub 2010 Jan 11. 20065296 ( Full Text )

A critical role for Apc in hematopoietic stem and progenitor cell survival. Qian Z, Chen L, Fernald AA, Williams BO, Le Beau MM (2008 Sep) J Exp Med. 2008 Sep 1;205(9):2163-75. doi: 10.1084/jem.20080578. Epub 2008 Aug 25. 18725524 ( Full Text )

Cancer: hay in a haystack. Shannon KM, Le Beau MM(2008 Jan) Nature. 2008 Jan 17;451(7176):252-3. doi: 10.1038/451252a. 18202630

Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders. Joslin JM, Fernald AA, Tennant TR, Davis EM, Kogan SC, Anastasi J, Crispino JD, Le Beau MM (2007 Jul) Blood. 2007 Jul 15;110(2):719-26. Epub 2007 Apr 9. 17420284 ( Full Text )

Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Smith SM, Le Beau MM, Huo D, Karrison T, Sobecks RM, Anastasi J, Vardiman JW, Rowley JD, Larson RA(2003 Jul) Blood. 2003 Jul 1;102(1):43-52. Epub 2003 Mar 6. 12623843