The primary goal of this project is to improve treatment outcomes and cure rates of patients with acute myelogenous leukemia (AML) by developing novel, non-genotoxic therapeutic strategies that maximize the induction of leukemia cell apoptosis. TP53 is the master regulator of apoptosis that is frequently inactivated by overexpression of MDM2. Restoration of p53 activity by inhibition of MDM2-p53 interaction with non-genotoxic small molecule inhibitors (Nutlin-3a, RG7112, MI-63) dramatically increases cellular p53 levels and induces apoptosis. During the past funding period, we have generated pre-clinical and clinical evidence to support this concept. While much p53 in AML is localized in the cytoplasm, only nuclear p53 can function as transcription factor. Exportini (CRM1) is the major nuclear transporter of p53. Preliminary data suggest that CRM1 overexpression is associated with poor prognosis in AML. SINEs (selective inhibitors of nuclear export) are new, potent, irreversible and selective small molecule inhibitors of CRM1 [5, 6]. Our overall hypothesis is that nuclear retention of p53 by CRMI inhibition and non- genotoxic activation of p53 by inhibition of MDM2 will induce/enhance apoptosis in AML. in addition, we hypothesize that p53 is an important determinant of microenvironmental function.
In Aim 1 we will test the hypothesis that blockade of p53 nuclear export by CRMI inhibition in AML enhances apoptosis induced by M0M2 inhibition. We reported that AML cells express p53 predominantly in the cytoplasm and hypothesize that CRMI inhibition results in nuclear accumulation and activity of p53, thereby enhancing p53-mediated transcription- dependent apoptosis. SINEs have minimal toxicities in normal human cells, including hematopoietic cells in vitro and in vivo. Our preliminary data show that SINEs induce cell death in AML in a p53-dependent manner. We will investigate if nuclear retention of p53 by CRMI inhibition synergizes with accumulation of p53 by MDM2 inhibition to induce apoptosis in AML.
In Aim 2 we will investigate the role of p53 activation by MDM2 and CRMI inhibition in the bone marrow microenvironment. Bone marrow stromal cells protect AML cells from various anti-leukemic agents, but the MDM2 inhibitor Nutlin-3a or SINE KPT-185 kill AML cells even in the presence of
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