Matt Christopher, M.D., Ph.D.

Assistant Professor
Internal Medicine
Oncology

Cancer Biology Program
Molecular Cell Biology Program
Developmental, Regenerative and Stem Cell Biology Program

  • christopherm@wustl.edu

  • Improve outcomes for patients with acute myeloid leukemia (AML) and other hematopoietic malignancies utilizing genomic and molecular biology techniques

Research Abstract:

The principle goal of our lab is to use genomic and molecular biology techniques to improve outcomes for patients with acute myeloid leukemia (AML) and other hematopoietic malignancies. We are currently pursuing three projects that focus on different aspects of leukemia pathogenesis, diagnosis, and treatment.

In the first project, we are studying the role of the transcription factor WT1 in hematologic malignancies. Expressed widely during development, WT1 is not normally expressed in hematopoietic cells, however it is expressed at high levels in a wide range of blood cancers. In addition, roughly 10% of patients with AML have mutations in WT1, and up to 25% of patients with Acute promyelocytic leukemia (a subtype of AML associated with the PML-RARA fusion
mutation) have co-occuring mutations in WT1, suggesting that WT1 mutations may also contribute to disease progression in these cases. Through lentiviral overexpression and CRISPR-mediated gene disruption, we have generated gain and loss-of-function models of WT1 in both mouse and human hematopoietic progenitor cells (HPC). Interestingly, we have observed that introduction of PML-RARA and a wide range of other leukemia-associated mutations in HPC leads to a rapid and robust activation of WT1 expression in these cells, suggesting that WT1 activation may be an early event in leukemia progression.

Our second project is a clinical-translational project testing whether a sensitive, next-generation sequencing platform can predict leukemia relapse after transplantation before it becomes clinically evident. In a preliminary experiment using a PCR amplicon sequencing approach, leukemic variants could be detected in bone marrow samples obtained ~6 months before clinical relapse. To extend these studies, we have made use of an institutional, clinically validated error-corrected sequencing platform (Haloplex, Illumina) to test if AML relapse after transplantation can be detected with improved lead time compared to single tandem repeat (STR) testing, the method used for early detection of relapse at the majority of centers. We are currently testing this approach retrospectively on samples from 40 patients who relapsed after transplant and 40 non-relapsed controls.

Finally, the third main project builds on our recent observation that in AML cells from patients relapsing after hematopoietic stem cell transplant (HCT), a number of immune genes are significantly dysregulated, including genes involved in innate immunity, cell trafficking and adhesion, and-strikingly-genes encoding MHC class II (MHCII). Since HCT is considered to work in part through donor T cell reactivity toward recipient hematopoietic cells (the "graft-versus-leukemia" effect), downregulation of MHCII and loss of antigen presentation by AML cells to donor T cells may contribute to AML relapse after HCT. Consistent with this, AML samples from patients who relapsed after stem cell transplantation with low MHCII expression failed to stimulate third-party donor T cells in vitro, in contrast to relapse AML cells with normal MHCII expression. Intriguingly, we observed decreased expression of CIITA, a transcriptional transactivator that regulates MHCII genes, associated with increased DNA methylation in a CIITA regulatory region in intron 1, suggesting a model wherein epigenetic changes in the CIITA
locus that occur after transplantation leads to downregulation of MHCII genes, contributing to relapse. Most importantly, downregulation of CIITA and MHCII genes was reversible after treatment with interferon gamma, suggesting a therapeutic strategy to restore MHCII expression and AML cell sensitivity to the graft-versus-leukemia effect. Currently, we are using mouse models of allogeneic stem cell transplantation to test the effect of CIITA overexpression and deletion on MHCII expression and the graft-versus-leukemia effect. Finally, we are testing
whether restoration of MHCII expression on relapsed AML cells restores sensitivity to donor T cells in a pre-clinical, mouse xenograft model of AML. Future experiments will make use of these models to explore the roles of innate immune and cell adhesion genes in posttransplantation relapse.

Selected Publications:

Immune Escape of Relapsed AML Cells After Allogeneic Transplantation
Christopher MJ, Petti AA, Rettig MP, Miller CA, Chendamarai E, Duncavage EJ, Klco JM, Helton NM, O'Laughlin M, Fronick CC, Fulton RS, Wilson RK, Wartman LD, Welch JS, Heath SE, Baty JD, Payton JE, Graubert TA, Link DC, Walter MJ, Westervelt P, Ley TJ, DiPersio JF
N Engl J Med 2018 Dec 13;379(24):2330-2341

Mutation Clearance After Transplantation for Myelodysplastic Syndrome
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
N Engl J Med 2018 Sep 13;379(11):1028-1041

DNMT3A(R882)-Associated Hypomethylation Patterns Are Maintained in Primary AML Xenografts, but Not in the DNMT3A(R882C) OCI-AML3 Leukemia Cell Line
Chen D, Christopher M, Helton NM, Ferguson I, Ley TJ, Spencer DH
Blood Cancer J 2018 Apr 4;8(4):38

Comprehensive Genomic Analysis Reveals FLT3 Activation and a Therapeutic Strategy for a Patient With Relapsed Adult B-Lymphoblastic Leukemia
Griffith M, Griffith OL, Krysiak K, Skidmore ZL, Christopher MJ, Klco JM, Ramu A, Lamprecht TL, Wagner AH, Campbell KM, Lesurf R, Hundal J, Zhang J, Spies NC, Ainscough BJ, Larson DE, Heath SE, Fronick C, O'Laughlin S, Fulton RS, Magrini V, McGrath S, Smith SM, Miller CA, Maher CA, Payton JE, Walker JR, Eldred JM, Walter MJ, Link DC, Graubert TA, Westervelt P, Kulkarni S, DiPersio JF, Mardis ER, Wilson RK, Ley TJ
Exp Hematol 2016 Jul;44(7):603-13

A Genomic Analysis of Philadelphia Chromosome-Negative AML Arising in Patients With CML
Krysiak K*, Christopher MJ*, Skidmore ZL, Demeter RT, Magrini V, Kunisaki J, O'Laughlin M, Duncavage EJ, Miller CA, Ozenberger BA, Griffith M, Wartman LD, Griffith OL (*shared first authorship)
Blood Cancer J 2016 Apr 8;6:e413

Last Updated: 8/14/2019 1:59:48 PM

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