Matthew J. Walter, M.D.

Internal Medicine

Molecular Genetics and Genomics Program
Cancer Biology Program

  • 314-362-9409

  • 314-362-9405

  • 314-362-9333

  • Southwest Tower, Room 613L



  • cancer, functional genomics, gene expression profiling, hematopoiesis, stem cells, tumor biology

  • Genetics and genomics of blood cancer: mutation discovery and mouse models

Research Abstract:

The main interest of our laboratory is the discovery and characterization of gene mutations in patients with myelodysplastic syndrome (MDS) with the long-term goal of understanding the molecular mechanisms that control abnormal hematopoiesis. MDS results from the expansion of one or more dominant hematopoietic clones that contain initiating somatic mutations, while transformation from MDS to acute myeloid leukemia (AML) occurs as these clones accumulate additional progression factors (including point mutations in genes and cytogenetic abnormalities).

Current projects include the following:
1. Tumor clonal heterogeneity.
Gene mutations are identified in the genomes of hematopoietic cells from patients with MDS and AML using next generation sequencing technology, including whole genome sequencing. Somatic mutations are used to decipher the clonal architecture of MDS and AML samples (ie, founding clones and subclones). The functional significance of recurrently mutated genes is then studied using primary human hematopoietic cells and mouse models to understand the mechanisms of disease pathogenesis.

2. Monitoring tumor burden using next-generation sequencing.
Gene mutations are identified in patient samples using whole genome and exome sequencing. The abundance of tumor-specific mutations are tracked in serial samples using error-corrected sequencing during treatment to objectively monitor tumor burden and treatment response. The prognostic utility of these approaches are being tested in clinical trials to improve patient outcomes.

3. The role of splicing gene mutations in MDS pathogenesis.
Ongoing projects are focused on understanding the mechanism of MDS initiation and progression induced by mutations in genes that participate in pre-mRNA splicing identified by our group and others. Spliceosome gene mutations occur in 50% of MDS patients. Functional splicing assays, next-generation sequencing technology, and hematopoietic assays will be used to study primary human cells and mouse models harboring mutations. Preclinical cell and mouse models are being used to test novel approaches to selectively kill spliceosome mutant cells with the goal of introducing new therapies into clinical trials for MDS patients.

All these studies involve state of the art technologies and incorporate functional genomics, bioinformatics, next-generation sequencing, stem cell and tumor biology, and mouse models of disease to study hematopoiesis.

Selected Publications:

1: Duncavage EJ, Jacoby MA, Chang GS, Miller CA, Edwin N, Shao J, Elliott K, Robinson J, Abel H, Fulton RS, Fronick CC, O`Laughlin M, Heath SE, Brendel K, Saba R, Wartman LD, Christopher MJ, Pusic I, Welch JS, Uy GL, Link DC, DiPersio JF, Westervelt P, Ley TJ, Trinkaus K, Graubert TA, Walter MJ. Mutation Clearance after Transplantation for Myelodysplastic Syndrome. N Engl J Med. 2018 Sep 13;379(11):1028-1041. doi: 10.1056/NEJMoa1804714. PubMed PMID: 30207916.

2: Jacoby MA, Duncavage EJ, Chang GS, Miller CA, Shao J, Elliott K, Robinson J, Fulton RS, Fronick CC, O`Laughlin M, Heath SE, Pusic I, Welch JS, Link DC, DiPersio JF, Westervelt P, Ley TJ, Graubert TA, Walter MJ. Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant. JCI Insight. 2018 Mar 8;3(5). pii: 98962. doi: 10.1172/jci.insight.98962. [Epub ahead of print] PubMed PMID: 29515031; PubMed Central PMCID: PMC5922277.

3: Uy GL, Duncavage EJ, Chang GS, Jacoby MA, Miller CA, Shao J, Heath S, Elliott K, Reineck T, Fulton RS, Fronick CC, O`Laughlin M, Ganel L, Abboud CN, Cashen AF, DiPersio JF, Wilson RK, Link DC, Welch JS, Ley TJ, Graubert TA, Westervelt P, Walter MJ. Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy. Leukemia. 2017 Apr;31(4):872-881. doi: 10.1038/leu.2016.282. Epub 2016 Oct 14. PubMed PMID: 27740633; PubMed Central PMCID: PMC5382101.

4: Shirai CL, White BS, Tripathi M, Tapia R, Ley JN, Ndonwi M, Kim S, Shao J, Carver A, Saez B, Fulton RS, Fronick C, O`Laughlin M, Lagisetti C, Webb TR, Graubert TA, Walter MJ. Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome. Nat Commun. 2017 Jan 9;8:14060. doi: 10.1038/ncomms14060. PubMed PMID: 28067246; PubMed Central PMCID: PMC5227701.

5: 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. doi: 10.1016/j.ccell.2015.04.008. PubMed PMID: 25965570; PubMed Central PMCID: PMC4430854.

6: 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. doi: 10.1038/leu.2013.58. Epub 2013 Feb 27. PubMed PMID: 23443460; PubMed Central PMCID: PMC3736571.

7: Walter MJ, Shen D, Ding L, Shao J, Koboldt DC, Chen K, Larson DE, McLellan MD, Dooling D, Abbott R, Fulton R, Magrini V, Schmidt H, Kalicki-Veizer J, O`Laughlin M, Fan X, Grillot M, Witowski S, Heath S, Frater JL, Eades W, Tomasson M, Westervelt P, DiPersio JF, Link DC, Mardis ER, Ley TJ, Wilson RK, Graubert TA. Clonal architecture of secondary acute myeloid leukemia. N Engl J Med. 2012 Mar 22;366(12):1090-8. doi: 10.1056/NEJMoa1106968. Epub 2012 Mar 14. PubMed PMID: 22417201; PubMed Central PMCID: PMC3320218.

8: Graubert TA, Shen D, Ding L, Okeyo-Owuor T, Lunn CL, Shao J, Krysiak K, Harris CC, Koboldt DC, Larson DE, McLellan MD, Dooling DJ, Abbott RM, Fulton RS, Schmidt H, Kalicki-Veizer J, O`Laughlin M, Grillot M, Baty J, Heath S, Frater JL, Nasim T, Link DC, Tomasson MH, Westervelt P, DiPersio JF, Mardis ER, Ley TJ, Wilson RK, Walter MJ. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet. 2011 Dec 11;44(1):53-7. doi: 10.1038/ng.1031. PubMed PMID: 22158538; PubMed Central PMCID: PMC3247063.

Last Updated: 9/24/2018 3:14:26 PM

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