Familial MDS/AML is a group of rare Mendelian disorders associated with strong predisposition to MDS and/or AML. The genetic basis of these disorders is explained in ~50% of these families by inherited variants in three genes {RUNX1, CEBPA, or GATA2). Affected carriers in these families develop MDS/AML with variable latency and incomplete penetrance, suggesting that cooperating somatic mutations are required for transformation. We hypothesize that there are additional high penetrance germline alleles that account for familial MDS/AML cases lacking known causal variants.
In Specific Aim 1, we will identify novel inherited genetic variants associated with familial MDS/AML. We have assembled a large number of MDS/AML kindreds (>40), with known causes identified in approximately half. We will use an innovative screen to exclude known causes in the remaining families and will then perform whole genome sequencing to identify novel variants in all cases with unexplained familial predisposition. We will identify variants that segregate with MDS/AML in these families and test for replication in other families. We will generate extended pedigrees for early-onset de novo AML cases, determine the extent of familial aggregation of MDS/AML and other cancers, and mine germline whole genome sequence data generated for these cases by other GAML projects to identify additional inherited risk alleles for AML. We will perform functional studies to characterize the effects of novel alleles on hematopoiesis.
In Specific Aim 2, we will define the landscape of somatic genetic alterations in familial MDS/AML. We will perform whole genome sequencing of paired tumor/normal samples from at least 50 cases of familial MDS/AML and compare the spectrum of somatic mutations in these cases to de novo and therapy-related MDS/AML. Knowledge gained from this project will inform our understanding ofthe biology of AML, and lead to better strategies for surveillance, early detection, and treatment of MDS/AML, including optimized stem cell donor selection in families with inherited susceptibility.

Public Health Relevance

Several rare syndromes cause strong familial predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). For approximately half of these families, the genetic cause is unknown. Identification of novel inherited variants and recurrent somatic mutations in familial MDS/AML will be helpful for genetic counseling, surveillance/early detection, and treatment, including appropriate donor selection for hematopoietic stem cell transplantation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Saint Louis
United States
Zip Code
Fisher, D A C; Malkova, O; Engle, E K et al. (2017) Mass cytometry analysis reveals hyperactive NF Kappa B signaling in myelofibrosis and secondary acute myeloid leukemia. Leukemia 31:1962-1974
Uy, G L; Duncavage, E J; Chang, G S et al. (2017) Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy. Leukemia 31:872-881
Cole, Christopher B; Russler-Germain, David A; Ketkar, Shamika et al. (2017) Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies. J Clin Invest 127:3657-3674
Spencer, David H; Russler-Germain, David A; Ketkar, Shamika et al. (2017) CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression. Cell 168:801-816.e13
Bandyopadhyay, Shovik; Li, Junjie; Traer, Elie et al. (2017) Cholesterol esterification inhibition and imatinib treatment synergistically inhibit growth of BCR-ABL mutation-independent resistant chronic myelogenous leukemia. PLoS One 12:e0179558
Duncavage, Eric J; Uy, Geoffrey L; Petti, Allegra A et al. (2017) Mutational landscape and response are conserved in peripheral blood of AML and MDS patients during decitabine therapy. Blood 129:1397-1401
Shirai, Cara Lunn; White, Brian S; Tripathi, Manorama et al. (2017) Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome. Nat Commun 8:14060
Schroeder, Mark A; Choi, Jaebok; Staser, Karl et al. (2017) The Role of Janus Kinase Signaling in Graft-Versus-Host Disease and Graft Versus Leukemia. Biol Blood Marrow Transplant :
Zhang, Jin; Griffith, Malachi; Miller, Christopher A et al. (2017) Comprehensive discovery of noncoding RNAs in acute myeloid leukemia cell transcriptomes. Exp Hematol 55:19-33
Ali, Alaa M; Weisel, Daniel; Gao, Feng et al. (2017) Patterns of infectious complications in acute myeloid leukemia and myelodysplastic syndromes patients treated with 10-day decitabine regimen. Cancer Med 6:2814-2821

Showing the most recent 10 out of 113 publications