FOXM1 Modulates Treatment Outcomesin Acute Myeloid Leukemia
thesisposted on 2020-08-01, 00:00 authored by Irum Khan
Acute Myeloid Leukemia (AML) patients with NPM1 mutations, known to cause aberrant cytoplasmic re-localization, demonstrate a superior response to standard chemotherapy treatment. Early data from my mentor Dr. Gartel’s lab established the importance of the physical interaction of these NPM and FOXM1 in cancer cells. We first wanted to link this well-documented favorable outcome of NPM1 mutant AML to the cytoplasmic re-localization and inactivation of FOXM1. We then went on to confirm the important role of FOXM1 in increased chemo-resistance in AML. A multi-institution retrospective study was conducted to link FOXM1 expression to clinical outcomes in AML. We established nuclear FOXM1 as an independent clinical predictor of chemotherapeutic resistance in intermediate-risk AML in a multivariate analysis incorporating standard clinicopathologic risk factors. Using in vitro assays we showed that manipulation of nuclear FOXM1 affected the clonogenic activity of AML cells. In order to further prove a potential role for FOXM1 in AML chemo-resistance, we induced a FOXM1-overexpressing transgenic mouse model of leukemia and demonstrated significantly higher residual disease after standard chemotherapy. This suggests that constitutive overexpression of FOXM1 in this model induces chemo-resistance. Finally, we performed proof of principle experiments using a currently approved drug ‘Ixazomib’ to target FOXM1 and demonstrated a therapeutic response in patient samples and animal models of AML that correlates with the suppression of FOXM1 and its transcriptional targets. The addition of low doses of Ixazomib increases sensitization of AML cells to standard chemotherapy. Our results underscore the importance of FOXM1 in AML treatment outcomes and suggest targeting it may have therapeutic benefit in combination with standard AML therapies.