Research Centers

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Graubert Lab

The Graubert laboratory focuses on the molecular basis of human blood cancers, including acute myeloid leukemia and myelodysplastic syndromes.

Timothy Graubert, MD
Jon and JoAnn Hagler Chair in Hematology-Oncology
Program Director, Hematologic Malignancies, Cancer Center

Research Summary

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.

Read the Graubert Lab's Annual report in full

Timothy Graubert, MD
Principal Investigator

Group Members

  • Amy Bertino, PhD
  • Emily Silva

(in St. Louis)
Masayo Izumi
Megan Janke*
Elise Lu*
Dipika Mohan*
Theresa Okeyo-Owuor*
Manorama Tripathi, PhD

*students

Research Projects


While at Washington University in St. Louis, the Graubert laboratory was part of a large team of investigators who helped pioneer the use of genome sequencing technology to gain insights into the genetic basis of human cancer and to use this information to improve prognostic models and to identify novel targets for therapy.  This group published the first complete genome sequence of a human cancer (acute myeloid leukemia) in 2008 and in subsequent publications described novel recurrent mutations in IDH2 and DNMT3A that have prognostic significance in acute myeloid leukemia. Clonal evolution from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML).  Whole genome sequencing at the time of MDS diagnosis (left arrow) in a representative patient identified a founding clone comprising ~52% of the bone marrow cellularity and a subclone derived from the founding clone in ~22% of cells.  When this patient progressed to AML (right arrow), the original clones were still present and had spawned three new subclones that were dominant in the bone marrow at this time point.

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 malignant 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.

Postdoctoral Research Fellow
Cancer Biology

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, MD
Massachusetts General Hospital Cancer Center/Harvard Medical School


 

Selected publications

The Cancer Genome Atlas Research Network.  The Genomic and Epigenomic Landscape of Adult de novo Acute Myeloid Leukemia.  N Engl J Med. 368:2059-2074, 2013 May 30.

MJ Walter, D Shen, J Shao, L Ding, BS White, C Kandoth, CA Miller, B Niu, MD McLellan, ND Dees, R Fulton, K Elliott, S Heath, M Grillot, P Westervelt, DC Link, JF DiPersio, ER Mardis, TJ Ley, RK Wilson, and TA Graubert.  Clonal Diversity of Recurrently Mutated Genes in Myelodysplastic Syndromes.  Leukemia. 27:1275-82, 2013 Feb 27.

Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, Wartman LD, Lamprecht TL, Liu F, Xia J, Kandoth C, Fulton RS, McLellan MD, Dooling DJ, Wallis JW, Chen K, Harris CC, Schmidt HK, Kalicki-Veizer JM, Lu C, Zhang Q, Lin L, O’Laughlin MD, McMichael JF, Delehaunty KD, Fulton LA, Magrini VJ, McGrath SD, Demeter RT, Vickery TL, Hundal J, Cook LL, Swift GW, Reed JP, Alldredge PA, Wylie TN, Walker JR, Watson MA, Heath SE, Shannon WD, Varghese N, Nagarajan R, Payton JE, Baty JD, Kulkarni S, Klco JM, Tomasson MH, Westervelt P, Walter MJ, Graubert TA, DiPersio JF, Ding L, Mardis ER, Wilson RK.  The Origin and Evolution of Mutations in Acute Myeloid Leukemia. Cell. 150(2):264-278.  2012 July 20.

MJ Walter, D Shen, L Ding, J Shao, DC Koboldt, K Chen, DE Larson, MD McLellan, D Dooling, R Abbott, R Fulton, V Magrini, H Schmidt, J Kalicki-Veizer, M O’Laughlin, X Fan,  M Grillot, S Witowski, S Heath, JL Frater, W Eades, M Tomasson, P Westervelt, JF DiPersio, DC Link, ER Mardis, TJ Ley, RK Wilson, and TA Graubert.  Clonal Architecture of Secondary Acute Myeloid Leukemia.  N Engl J Med.  366(12):1090-8.  2012 Mar 22.

TA Graubert, D Shen, L Ding, T Okeyo-Owuor, C L Lunn, J Shao, K Krysiak, CC Harris, DC Koboldt, DE Larson, MD McLellan, DJ Dooling, RM Abbott, RS Fulton, H Schmidt, J Kalicki-Veizer, M O’Laughlin, M Grillot, J Baty, S Heath, JL Frater, T Nasim, DC Link, MH Tomasson, P Westervelt, JF DiPersio, ER Mardis, TJ Ley, RK Wilson, and MJ Walter.  Recurrent Mutations in the U2AF1 Splicing Factor in Myelodysplastic Syndromes.  Nature Genetics. 44:53-5.  2011 Dec 11.

Graubert Lab

Buidling 149
15th Street
Charlestown Navy Yard
Charlestown, MA 02129

Phone: 617-726-7805


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