Leukemogenesis
Myelofibrosis (MF) is a rare hematologic disorder characterized by constitutional symptoms, cytopenia, splenomegaly, bone marrow fibrosis, and a propensity for transformation to acute myeloid leukemia (AML). Approximately 85% of MF cases are driven by mutations in JAK2, MPL, and CALR genes. However, the underlying mechanisms in MF patients who are lacking these driver mutations are largely unknown. We recently discovered that the MYC-alarmin pathway can drive MF independent of mutations in JAK2 pathway in subgroup of MF patients. We are actively investigating (1) Underlying mechanisms as to how alarmins are upregulated, (2) Cell-cell interactions mediated by these alarmins in BM niche cells, (3) Interplay between the MYC-alarmin axis and other co-mutations, (4) Systemic effects of MYC-alarmin mediated inflammation, and (5) Mechanisms of MF transformation into AML, an aggressive form of myeloid malignancy.
New therapeutics
MYC oncoproteins regulate transcription of genes directing cell proliferation, metabolism, and tumorigenesis. A verity of alterations drive MYC expression in MDS, MPN, and AML. We recently discovered that AML and myeloid progenitor cell growth and survival rely on MYC-directed suppression of Transcriptional Factor EB (TFEB), a master regulator of the autophagy-lysosome pathway. Notably, although originally identified as an oncogene, TFEB functions as a tumor suppressor in AML, where it provokes AML cell differentiation and death. These responses reflect TFEB control of myeloid epigenetic programs by inducing expression of isocitrate dehydrogenase-1 (IDH1) and IDH2, resulting in global hydroxylation of 5-methylcytosine. Finally, activating the TFEB-IDH1/2-TET2 axis is revealed as a targetable vulnerability in AML. Thus, epigenetic control by an MYC-TFEB circuit dictates myeloid cell fate and is essential for maintenance of AML. We are actively investigating to develop small molecules inhibitors targeting MYC and IDH1/2, as well as agents that activate TFEB.
Personalized medicine
AML is a heterogeneous hematologic malignancy driven by somatic mutations and chromosomal abnormalities. Despite the widespread use of intensive chemotherapies and target therapies (e.g., Venetoclax and hypomethylating agents) for fit and unfit patients, respectively, the clinical response to these regimens varies significantly based on underlying genetics of individual patient. Our laboratory is dedicated to identifying and characterizing the molecular determinants that influence clinical outcomes in AML patients. We achieve this by integrating data from scRNA-seq, targeted exome sequencing, analysis of copy number alterations, and examination of DNA methylation patterns in primary bone marrow or peripheral blood samples collected longitudinally from AML patients. Ultimately, we corroborate these findings through validation using various models including in vitro, ex vivo, and in vivo studies, which incorporate patient-derived xenograft models.