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Timothy Graubert, MDJon and JoAnn Hagler Chair in Hematology-OncologyProgram Director, Hematologic Malignancies, Cancer Center
The Graubert laboratory focuses on the molecular basis of human blood cancers, including acute myeloid leukemia and myelodysplastic syndromes. The laboratory utilizes a variety of genomic platforms to interrogate primary samples from patients with myeloid malignancies to identify inherited and somatic mutations that drive these diseases. The goal of these studies is to gain insight into the biological basis of myeloid leukemias, and to improve strategies for diagnosis, risk stratiﬁcation, and targeted therapy.
Timothy Graubert, MDPrincipal Investigator
Clonal heterogeneity of myelodysplastic syndromes
Myelodysplastic syndromes are the most common form of acquired bone marrow failure in adults. Despite the ineffective hematopoiesis that is characteristic of this disease in its early stages, we found through whole genome sequencing that nearly all cells in the bone marrow of these patients are clonally derived (see Figure). When patients evolve to acute myeloid leukemia (which occurs in approximately one third of cases), new subclonal populations emerge that are derived from the original (“founding”) clone. These ﬁndings raise the possibility that the prognostic value of recurrent mutations in myelodysplastic syndrome and the efficacy of therapies that target these mutations may depend not only on the presence or absence of these mutations, but also on their position within the clonal hierarchy of this disease.
RNA splicing defects at the root of myelodysplastic syndromes
We and several other groups discovered recurrent somatic mutations in genes encoding core components of the RNA splicing complex (the “spliceosome”) in patients with myelodysplastic syndrome. Mutations in this pathway tend to be mutually exclusive, suggesting that more than one splicing gene mutation in a cell provides no additional selective advantage, or is deleterious to the clone. We have focused on U2AF1 which encodes a component of the U2 snRNP that binds to the AG dinucleotide at the 3’ intronic splice acceptor site. Mutations in U2AF1 arise early in the pathogenesis of myelodysplastic syndromes (in the founding clone) and affect almost exclusively two codons in predicted zinc ﬁnger domains. We have shown that the most common mutation (S34F) has gain-of-function activity in splicing assays. Current work in the Graubert laboratory is focused on comprehensive analysis of the impact of U2AF1 mutations on splicing, generation of mouse models of these mutations, and testing the hypothesis that splicing gene mutations create a dependency in cells that confers sensitivity to the cytotoxic effects of small molecule modulators of the splicing complex.
Inherited predisposition to myelodysplastic syndrome/acute myeloid leukemia
Acute myeloid leukemia and myelodysplastic syndromes are usually sporadic, late-onset cancers, but in rare instances (<1%) these diseases aggregate in families. In these families, predisposition to acute myeloid leukemia/myelodysplastic syndrome may be a consequence of an inherited bone marrow failure syndrome, but in other cases these are highly penetrant, autosomal dominant, Mendelian disorders. Three genes (RUNX1, GATA2, CEBPA) explain roughly half of these Mendelian cases. The genetic basis in the remaining half is not yet known. Furthermore, the latency and incomplete penetrance of acute myeloid leukemia/myelodysplastic syndrome in mutation carriers suggest that acquisition of cooperating somatic mutations is required for alignant transformation. We have accumulated a large panel of samples from affected and unaffected members of these families. Ongoing studies in the Graubert laboratory are focused on identiﬁcation of novel germline variants in families that lack known predisposing factors and characterization of the landscape of cooperating somatic mutations that arise in these cases. This information is important for genetic counseling in these families, for selection of optimal bone marrow transplant donors, and to increase our understanding of the biological basis of acute myeloid leukemia and myelodysplastic syndromes.
A Postdoctoral Research Fellow position is available to study the molecular basis of human myeloid leukemias. The candidate must have recently received a PhD or MD PhD degree in the biological sciences, and be highly motivated and well versed in basic molecular biology, cell biology, and biochemical techniques with special interests in hematopoiesis, genetics, and mouse models of human leukemia. The Fellow will have simultaneous academic appointments at the Massachusetts General Hospital, Harvard Medical School, and the Broad Institute. The laboratory provides a rich intellectual environment within a group of highly collaborative investigators, with full integration into the large research communities of the Massachusetts General Hospital, Harvard University, and the Broad Institute.
Interested candidates should e-mail a brief cover letter and CV to:
Timothy Graubert, MDMassachusetts General Hospital Cancer Center/Harvard Medical School
Shirai CL, Ley JN, White BS, Kim S, Tibbitts J, Shao J, Ndonwi M, Wadugu B, Duncavage EJ, Okeyo-Owuor T, Liu T, Griffith M, McGrath S, Magrini V, Fulton RS, Fronick C, O’Laughlin M, Graubert TA, Walter MJ. Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo. Cancer Cell. 2015, May 11;27(5):631-43.
Okeyo-Owuor T, White BS, Chatrikhi R, Mohan DR, Kim S, Griffith M, Ding L, Ketkar-Kulkarni S, Hundal J, Laird KM, Kielkopf CL, Ley TJ, Walter MJ, Graubert TA. U2AF1 mutations alter sequence speciﬁcity of pre-mRNA binding and splicing. Leukemia. 2015 Apr;29(4):909-17.
Hughes AEO, Magrini V, Demeter R, Miller CA, Fulton R, Fulton LL, Eades WC, Elliott K, Heath S, Westervelt P, Ding L, Conrad DF, White BS, Shao J, Link DC, DiPersio JF, Mardis ER, Wil-son RK, Ley TJ, Walter MJ, Graubert TA. Clonal architecture of secondary acute myeloid leukemia deﬁned by single-cell sequencing. PLoS Genet. 2014 Jul 10;10(7):e1004462.
Klco JM, Spencer DH, Miller CA, Griffith M, Lamprecht TL, O’Laughlin M, Fronick C, Magrini V, Demeter RT, Fulton RS, Eades WC, Link DC, Graubert TA, Walter MJ, Mardis ER, Dipersio JF, Wilson RK, Ley TJ. Func-tional heterogeneity of genetically deﬁned subclones in acute myeloid leukemia. Cancer Cell. 2014 Mar 17;25(3):379-92.
The Cancer Genome Atlas Research Network. The Genomic and Epig-enomic Landscape of Adult de novo Acute Myeloid Leukemia. N Engl J Med. 368:2059-2074, 2013 May 30.
Walter MJ, Shen D, Shao J, Ding L, White BS, Kandoth C, Miller CA, Niu B, McLellan MD, Dees ND, Fulton R, Elliot K, Heath S, Grillot M, Westervelt P, Link DC, DiPersio JF, Mardis E, Ley TJ, Wilson RK, Graubert TA. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. Leukemia. 2013 Jun;27(6):1275-82.
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