Stress Response Gadd45a Gene As Tumor Suppressor In Myc Expressing Myeloid Cells Is Cytokine Specific

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC MYC, which regulates proliferation, apoptosis/survival and differentiation, is implicated in the etiology of a wide variety of hematologic malignancies. Multiple cooperating molecular pathways of cell survival and apoptosis determine if a cell lives or dies, and understanding how c-MYC interfaces with these pathways to influence the survival of cells is important to understand tumor initiation and progression, and response of tumors to different treatment regimens. Previously, this laboratory has shown that deregulated c-MYC blocks terminal myeloid differentiation and prematurely recruits both the Type I and Type II CD95/Fas apoptotic pathways, promoting an incompletely penetrant apoptotic response. Here we provide data to show that the response of myeloid cells to deregulated MYC expression depends on the status of the Gadd45 family of stress response genes. The gadd45 gene family plays pivotal roles as stress sensors that modulate signaling in response to physiological and environmental stressors, also modulating susceptibility of cells for transformation in vitro and tumor development in vivo. Gadd45 behaves as either tumor suppressor or oncogene depending upon the transforming oncogene and the cell type. To elucidate the role Gadd45a plays in response to the proto-oncogene c-MYC in myeloid cells, bone marrow (BM) cells from wild type (WT) and Gadd45a null mice were retrovirally infected to constitutively express c-MYC. We showed that Gadd45a null BM expressing constitutive c-MYC exhibited less apoptosis than its WT counterpart in expansion media (IL-3, IL-6, SCF), demonstrating that Gadd45a is required for optimal MYC mediated apoptosis. In addition, enhancement of cell cycle progression was observed. Therefore, loss of gadd45a in conjunction with constitutive MYC expression results in enhanced proliferation. Furthermore, in GM-CSF treated cells the MYC-mediated block/delay in differentiation was more extensive in the Gadd45a null cells compared to similarly treated WT cells. Interestingly, the percent of apoptosis was higher in the Gadd54a null cells expressing constitutive MYC as compared to the WT counterpart. This observation was in contrast to the results seen in expansion media, suggesting that the role Gadd45a plays in the presence of deregulated MYC may be cytokine specific. In addition, preliminary data also suggests that Gadd45a null bone marrow expressing deregulated c-myc loose responsiveness to MCSF and GCSF. Data will be presented to explain how gadd45 regulates both the apoptotic response, depending upon the specific cytokine, and differentiation of MYC-expressing myeloid cells. Furthermore, experiments to determine how loss of gadd45a influences MYC-mediated leukemia, including assessing the effect of manipulating the cytokine milieu, are currently underway. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3099.