• Source: Scopus
20012021

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Research interests

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.

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