WASHINGTON UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICINE

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An orphan box H/ACA snoRNA targeted by the t(4;14) chromosomal translocation in multiple myeloma

Multiple myeloma (MM) is an incurable malignancy of immunoglobulin secreting plasma B-cells. The genetics of this cancer type have remained unclear. The Tomasson lab is studying the t(4;14) chromosomal translocation, found in 15% of MM cases and associated with poor-prognosis. The translocation up-regulates the WHSC1/MMSET gene which encodes a histone methyltransferase, but we found that the t(4;14) also induces a novel box H/ACA class snoRNA of unknown function. Ribosomal protein genes were down-regulated in strong association with the t(4;14) translocation in MM patient samples (p=4.78e-20), and ACA11 appears to be part of a ribonucleoprotein (RNP) complex involved in the processing of ribosomal protein gene transcripts.

We aim to (1) confirm the proteins in the ACA11 RNP complex in MM cells harboring the t(4;14) translocation, (2) characterize the function of ACA11RNP in ribosomal biogenesis, and (3) evaluate the effects of ACA11 and ACA11/MMSET over-expression in B-lineage hematopoietic cells on growth and transformation. Together these experiments will allow us to devise better treatments for patients with originally poor-outcome t(4;14)-positive MM.

Targeting the Myc oncogene product in myeloma using nanoparticle technology

We are working on a second project in the lab involving multiple myeloma (MM). MM is the second most common blood malignancy in the United States, and accounts for 1% of cancer deaths. Despite recent advances, the 5-year survival rate in patients with MM is less than 40%. MM responds well to chemotherapy and remissions occur in the majority of MM patients, but all patients eventually relapse and die from progressive disease within 6 years. If the residual post-remission cells or their activation to progressive disease could be disrupted with novel targeted therapies, it would have a significant impact on the care and treatment of MM patients, particularly male veterans who are at 51% increased risk of MM compared to the general public.

Myc is a DNA regulating factor overproduced in 50-80% of human cancers and associated with 100,000 US cancer deaths per year. During the last several years, the concept of disrupting Myc interaction as a therapeutic mechanism to treat blood cancers has been demonstrated with in vitro model systems, but those agents have systematically proven ineffective in animals. We hypothesize that a novel c-Myc inhibitor linked to MM-targeted lipid-based nanoparticles will effectively seek and destroy myeloma cells. Our group has experience testing new myeloma treatments in mouse models that have been chosen for their close emulation of human myeloma bone disease and progression.

This project will produce a new-targeted treatment for patients with multiple myeloma. The technology we are developing theoretically will also work on other cancers that express VLA4 and Myc, such as myeloid leukemia and breast cancer, which also metastasize to bone.

Cytoplasmic tyrosine kinase gene expression in AML and normal myeloid cells RNA isolated from unfractionated AML bone marrow samples or from normal human bone marrow CD34+ cells, flow-sorted promyelocytes, and flow-sorted polymorphonuclear leukocytes was hybridized to Affymetrix U133 Plus 2 microarrays. Expression of cytoplasmic tyrosine kinase genes in our discovery set AML samples is rank-ordered from the highest to lowest levels of mean expression. AML samples are arranged by FAB classification. Expression levels are based on scaled signal intensity values for each probe set, with a value of 0 represented in green and 10 000 or greater as red. From: Tomasson MH, et al. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood 2008 May 1;111(9):4797-808

Education

1986	B.A., Wesleyan University, Middletown, CT
1992	M.D., Stanford University, Stanford, CA

Postdoctoral Training

1992-1998	Research Training Pathway, American Board of Internal Medicine
1992-1994	Internship and Residency in Internal Medicine, Stanford University Hospital, Stanford, CA
1994-1998	Fellowship in Hematology/Oncology, Massachusetts General Hospital, Boston, MA
1997-1998	Rotating Clinical/Research Fellow in Medicine, Brigham and Women's Hospital, Boston, MA
1998-2000	Research Fellow in Medicine, Brigham and Women's Hospital, Boston, MA

Academic Positions

1997-2000	Instructor in Medicine, Harvard Medical School, Boston, MA
2000-2007	Assistant Professor of Medicine and Genetics, Washington University, St. Louis, MO
2007-present	Associate Professor of Medicine and Genetics, Washington University, St. Louis, MO

Appointments & Committees

1992	Stanford University School of Medicine Admissions Committee
1993	Stanford University Committee on Residency Training Improvement
1996-1998	Dana-Farber/Partners CancerCare Internet Steering Committee
2000	American Society of Hematology, Internet Task Force
2002-2005	American Society of Hematology, Education Committee
2004-2007	Siteman Cancer Center Patient Review and Monitoring Committee (PRMC)
2008-present	Washington University Human Research Protection Office (IRB)

Board Certification

1992	Diplomate, American Board of Internal Medicine
1997	Diplomate, Subspecialty of Medical Oncology
1998	Diplomate, Subspecialty of Hematology

Honors & Awards

1983-1984	Muscular Dystrophy Association Summer Scholar
1986	Mansfield Freeman Prize for East Asian Studies
1990-1991	Medical Student Scholars Program Award
1997	Lori Strauss Leukemia Foundation Award
1998-2000	Leukemia Society of America Fellow
2004	Leukemia and Lymphoma Society, Translational Research Award
2007	Hope Award, American Cancer Society
2009	American Society for Clinical Investigation

Professional Societies

	American Society of Hematology
	American Society of Clinical Oncology
	American Cancer Society - Leukemia and Immunobiology Study Section

• Updated: March 19, 2012
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