Virginia & D.K. Ludwig Scholar for Cancer Research
Professor of Biology
KI Research Areas of Focus:
Virginia & D.K. Ludwig Scholar for Cancer Research
Professor of Biology
KI Research Areas of Focus:
"Our laboratory uses genetic approaches to identify the mechanistic bases of human disease pathology to develop effective strategies for intervention in human disease. Our efforts are focused in three major disease areas: trinucleotide repeat disorders particularly Huntington's disease (HD), cancer and cardiovascular disease. In the field of cancer, our research has included Wilms tumor, glioblastoma and melanoma, in which analysis of genetic alterations in germline DNA or in specific tumors identify pathways of particular significance to tumorigenesis."
Dr. Housman is a Ludwig Professor of Biology at MIT. He received both his B.A. and Ph.D. from Brandeis University in 1966 and 1971, respectively. Dr. Housman received the MIT Science Council Teaching Prize in 1992 and has been honored with the National Biotechnology Award from the National Conference on Biotechnology Ventures. He has also been Fellow of the American Association for the Advancement of Science since 1988 and the American Academy of Microbiology since 1994. Dr. Housman is a member of both the National Academy of Sciences and the Institute of Medicine of the National Academy of Sciences. He is a co-founder of Genzyme Genetics and former Somatix Therapy Corp; co-founded Kenna Technologies in 2000 and serves as its Adviser; and founded Integrated Genetics in 1980, which was acquired by Genzyme in 1989. He has served as Chairman, Scientific Founder, and Principal Scientific Advisor of Variagenics Inc. since 1993.
Our current research goals include identifying modifier genes which are responsible for variation in age of onset for HD. Prospective studies on extended HD families demonstrate that, other than the length of the CAG repeat sequence, modifier genes contribute significantly to determining the age of onset for HD. We are currently pursuing genetic linkage and association studies designed to identify these genes. In parallel, we are carrying out studies to identify genes which contribute to the timing of disease onset in mouse model systems for HD. We have also developed a series of model systems for the pathological effects of expanded polyglutamine repeats in Huntington's disease. Using these systems we have achieved the following goals:
Our current goals are focused on the identification and development of small molecules which show promise for therapeutic intervention in HD.
We have focused on several cancers including Wilms tumor, glioblastoma and melanoma, in which analysis of genetic alterations in germline DNA or in specific tumors identify pathways of particular significance to tumorigenesis.
My laboratory has been very active in the study of the WT1 tumor suppressor gene demonstrating its key role in tumorigneesis and kidney and urogeneital development. Most recently, we have focused on the role of the WT1 gene in hematopoiesis. WT1 has been utilized as a marker and proposed as a target for therapy for leukemia. We studied murine hematopoietic cells in which the WT1 gene has been inactivated by homologous recombination. We have found that cells lacking WT1 show deficits in hematopoietic stem cell function. We are currently exploring the impact of compromise to WT1 function on both normal and leukemic cells with the goal of gaining further understanding of the utility of WT1 as a marker and a target in therapy for leukemia.
We have focused on the receptor tyrosine kinase, c-Ros, which we have shown to be activated in a novel manner in glioblastoma. Through the characterization of a microdeletion on 6q22 in a glioblastoma, c-Ros can be activated via fusion to a novel Golgi apparatus-associated protein, Fig. The fused protein product (Fig-Ros) displays intrinsic kinase activity and is a potent oncogene. The transforming potential of the Fig-Ros fusion product resides in its ability to interact with and become localized to the Golgi apparatus. We are currently exploring the mechanisms by which a Golgi localized activated oncogene can cause cell transformation, and are initiating studies to identify small molecules which may serve as probes for Ros function in glioblastoma and the basis for possible therapeutic intervention for this tumor.
The goal of this project is to utilize high throughput genomic methodologies to identify genes contributing to various aspect of tumorigenesis in the InkD2/3 -/- tyr-rasV12G mouse melanoma model system. Our goal is to identify genes which contribute to the development of melanoma through studies of LOH in tumors and the mapping of modifier genes which accelerate or retard tumorigenesis in this model.
We are currently taking two major approaches to identifying genes which are significant contributors to cardiovascular disease. One approach involves population based association studies in which we are testing the association of specific SNP genotypes and haplotypes to cardiovascular disease and associated phenotypes. Our second approach involves proteomic analysis in a mouse model system. These studies currently focus on a mouse model for the cardiac pathology observed in myotonic dystrophy, We have utilized a proteomic approach including two dimensional gel electrophoresis and mass spectrometry to identify polypeptides which are altered in mobility in the hearts of mice deficient in the DMPK protein kinase, a gene whose expression is compromised in myotonic dystrophy and whose absence causes significant cardiac pathology in mice which lack this kinase. The goal of these studies is to determine the pathway to cardiac pathology which begins with the absence of function of the DMPK kinase and through this understanding elucidate the signaling pathways involving the DMPK kinase. Our further goal is to generalize this approach to other mouse models of cardiac pathology.
Wang ET, Cody NA, Jog S, Biancolella M, Wang TT, Treacy DJ, Luo S, Schroth GP, Housman DE, Reddy S, Lecuyer E, Burge CB. Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell. 2012 Aug 17;150(4):710-24.
Jun HJ, Acquaviva J, Chi D, Lessard J, Zhu H, Woolfenden S, Bronson RT, Pfannl R, White F, Housman DE, Iyer L, Whittaker CA, Boskovitz A, Raval A, Charest A. Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme. Oncogene. 2012 Jun 21;31(25):3039-50.
Crook ZR, Housman DE. Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice. Proc Natl Acad Sci U S A. 2012 May 8;109(19):7487-92.
Janas MM, Wang E, Love T, Harris AS, Stevenson K, Semmelmann K, Shaffer JM, Chen PH, Doench JG, Yerramilli SV, Neuberg DS, Iliopoulos D, Housman DE, Burge CB, Novina CD. Reduced expression of ribosomal proteins relieves microRNA-mediated repression. Mol Cell. 2012 Apr 27;46(2):171-86.
Parkesh R, Childs-Disney JL, Nakamori M, Kumar A, Wang E, Wang T, Hoskins J, Tran T, Housman D, Thornton CA, Disney MD. Design of a bioactive small molecule that targets the myotonic dystrophy type 1 RNA via an RNA motif-ligand database and chemical similarity searching. J Am Chem Soc. 2012 Mar 14;134(10):4731-42.
Acquaviva J, Jun HJ, Lessard J, Ruiz R, Zhu H, Donovan M, Woolfenden S, Boskovitz A, Raval A, Bronson RT, Pfannl R, Whittaker CA, Housman DE, Charest A. Chronic activation of wild-type epidermal growth factor receptor and loss of Cdkn2a cause mouse glioblastoma formation. Cancer Res. 2011 Dec 1;71(23):7198-206.
Crook ZR, Housman D. Huntington's disease: can mice lead the way to treatment? Neuron. 2011 Feb 10;69(3):423-35. doi: 10.1016/j.neuron.2010.12.035. Review. Erratum in: Neuron. 2011 Mar 10;69(5):1038.
Crittenden JR, Dunn DE, Merali FI, Woodman B, Yim M, Borkowska AE, Frosch MP, Bates GP, Housman DE, Lo DC, Graybiel AM. CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease. Hum Mol Genet. 2010 May 1;19(9):1756-65.
Wooten EC, Iyer LK, Montefusco MC, Hedgepeth AK, Payne DD, Kapur NK, Housman DE, Mendelsohn ME, Huggins GS. Application of gene network analysis techniques identifies AXIN1/PDIA2 and endoglin haplotypes associated with bicuspid aortic valve. PLoS One. 2010 Jan 21;5(1):e8830.
Williams AL, Housman DE, Rinard MC, Gifford DK. Rapid haplotype inference for nuclear families. Genome Biol. 2010;11(10):R108.
Weiss A, Abramowski D, Bibel M, Bodner R, Chopra V, DiFiglia M, Fox J, Kegel K, Klein C, Grueninger S, Hersch S, Housman D, R√©gulier E, Rosas HD, Stefani M, Zeitlin S, Bilbe G, Paganetti P. Single-step detection of mutant huntingtin in animal and human tissues: a bioassay for Huntington's disease. Anal Biochem. 2009 Dec 1;395(1):8-15.
Peter I, Kelley-Hedgepeth A, Huggins GS, Housman DE, Mendelsohn ME, Vita JA, Vasan RS, Levy D, Benjamin EJ, Mitchell GF. Association between arterial stiffness and variations in oestrogen-related genes. J Hum Hypertens. 2009 Oct;23(10):636-44.
Paganetti P, Weiss A, Trapp M, Hammerl I, Bleckmann D, Bodner RA, Coven-Easter S, Housman DE, Parker CN. Development of a method for the high-throughput quantification of cellular proteins. Chembiochem. 2009 Jul 6;10(10):1678-88.
Brocklebank D, Gay√°n J, Andresen JM, Roberts SA, Young AB, Snodgrass SR, Penney JB, Ramos-Arroyo MA, Cha JJ, Rosas HD, Hersch SM, Feigin A, Cherny SS, Wexler NS, Housman DE, Cardon LR; International-Venezuela Collaborative Research Group. Repeat instability in the 27-39 CAG range of the HD gene in the Venezuelan kindreds: Counseling implications. Am J Med Genet B Neuropsychiatr Genet. 2009 Apr 5;150B(3):425-9.
Jun HJ, Woolfenden S, Coven S, Lane K, Bronson R, Housman D, Charest A. Epigenetic regulation of c-ROS receptor tyrosine kinase expression in malignant gliomas. Cancer Res. 2009 Mar 15;69(6):2180-4.
Zhu H, Acquaviva J, Ramachandran P, Boskovitz A, Woolfenden S, Pfannl R, Bronson RT, Chen JW, Weissleder R, Housman DE, Charest A. Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2712-6.
Kelley-Hedgepeth A, Peter I, Montefusco MC, Levy D, Benjamin EJ, Vasan RS, Mendelsohn ME, Housman D, Huggins GS, Mitchell GF. The KCNMB1 E65K variant is associated with reduced central pulse pressure in the community-based Framingham Offspring Cohort. J Hypertens. 2009 Jan;27(1):55-60.
Williams BR, Prabhu VR, Hunter KE, Glazier CM, Whittaker CA, Housman DE, Amon A. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science. 2008 Oct 31;322(5902):703-9.
Mills JR, Hippo Y, Robert F, Chen SM, Malina A, Lin CJ, Trojahn U, Wendel HG, Charest A, Bronson RT, Kogan SC, Nadon R, Housman DE, Lowe SW, Pelletier J. mTORC1 promotes survival through translational control of Mcl-1. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10853-8.
Gayan J, Brocklebank D, Andresen JM, Alkorta-Aranburu G; US-Venezuela Collaborative Research Group, Zameel Cader M, Roberts SA, Cherny SS, Wexler NS, Cardon LR, Housman DE. Genomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds. Genet Epidemiol. 2008 Jul;32(5):445-53.
Peter I, Kelley-Hedgepeth A, Fox CS, Cupples LA, Huggins GS, Housman DE, Karas RH, Mendelsohn ME, Levy D, Murabito JM. Variation in estrogen-related genes associated with cardiovascular phenotypes and circulating estradiol, testosterone, and dehydroepiandrosterone sulfate levels. J Clin Endocrinol Metab. 2008 Jul;93(7):2779-85.
Kelley-Hedgepeth A, Peter I, Kip K, Montefusco M, Kogan S, Cox D, Ordovas J, Levy D, Reis S, Mendelsohn M, Housman D, Huggins G. The protective effect of KCNMB1 E65K against hypertension is restricted to blood pressure treatment with beta-blockade. J Hum Hypertens. 2008 Jul;22(7):512-5.
Chopra V, Fox JH, Lieberman G, Dorsey K, Matson W, Waldmeier P, Housman DE, Kazantsev A, Young AB, Hersch S. A small-molecule therapeutic lead for Huntington's disease: preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse. Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16685-9.
Bergmeier W, Goerge T, Wang HW, Crittenden JR, Baldwin AC, Cifuni SM, Housman DE, Graybiel AM, Wagner DD. Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III. J Clin Invest. 2007 Jun;117(6):1699-707.
Peter I, Huggins GS, Shearman AM, Pollak A, Schmid CH, Cupples LA, Demissie S, Patten RD, Karas RH, Housman DE, Mendelsohn ME, Vasan RS, Benjamin EJ. Age-related changes in echocardiographic measurements: association with variation in the estrogen receptor-alpha gene. Hypertension. 2007 May;49(5):1000-6.
Coufal M, Maxwell MM, Russel DE, Amore AM, Altmann SM, Hollingsworth ZR, Young AB, Housman DE, Kazantsev AG. Discovery of a novel small-molecule targeting selective clearance of mutant huntingtin fragments. J Biomol Screen. 2007 Apr;12(3):351-60.