Abstract 4194: APC and DIAPH1 collaborate to suppress myelodysplastic syndrome (MDS) pathogenesis

Myelodysplastic syndromes (MDS) are characterized by complex cytogenetic abnormalities, including loss of all or part of the long arm of chromosome 5 (5q). Known 5q tumor suppressors include APC1 and EGR1. APC is associated with familial colon cancer where it functions to suppress canonical Wnt signaling. Egr1 is a transcription factor that governs expression of tumor suppressor genes ranging from the p53 family to PTEN1. Adjacent to EGR1 is the DIAPH1 gene for the Rho GTPase effector formin DIAPH1. Knockout of Diaph1, Egr, or Apc in mice creates a range of MDS phenotypes. Likewise, mice with the multiple intestinal neoplasia (min/Apcmin) allele develop anemia and MDS most similar to the Diaph1 knockout phenotype. DIAPH1 builds linear actin filaments and stabilizes microtubule dynamics to establish and maintain cell polarity during adhesion, migration, and asymmetric cell division when activated by Rho GTPases, such as RhoB. Combinatorial deficiencies in RhoB (also a known tumor susceptibility gene) with Diaph1 exacerbates the Diaph1 MDS phenotype but not the rate of pathogenesis. RhoB-activated DIAPHs also signal and activate new gene expression by the myocardin-related (MRTF) and Mcm10/Agamous deficiens/ [serum response factor (SRF)] (MADS)-box transcription factors. MRTF-MADS registers changes in actin dynamics downstream of DIAPH1 to activate EGR1 expression through multiple serum response elements (SREs; recognized by SRF) within the EGR1 promoter. DIAPH1 also collaborates with APC in cytoskeletal remodeling as both proteins physically associate with and stabilize microtubules. APC can also nucleate new actin filaments that become processively elongated by DIAPH1. We examined interactions between APC and DIAPH1 signaling to SRF and in suppressing MDS pathogenesis. First, we found that both DIAPH1 and APC activate SRF- regulated gene expression. Consistent with biochemical data showing that DIAPH1 elongates APC-nucleated filaments, activation of SRF by APC relies upon DIAPH1. We bred Apcmin mice to our Diaph1 knockout mice and found that the MDS phenotype is significantly accelerated in Apcmin/Diaph1 knockout mice when compared to either the Apcmin or Diaph1 mutant phenotype. Pathological defects (dysplasia and anemia in peripheral blood and myeloid organs (spleen/bone marrow) requires at least 200 days to develop in either single mutant; combined mutations create aberrant peripheral blood cell pathology by 100 days of age. Consistent with early disease onset, mortality is accelerated in Apcmin /Diaph1-deficient mice. These novel studies show that genetic defects in Diaph1 and Apc synergize to effectively mimic 5q- MDS. Further, the data supports the idea that RhoB - DIAPH1/APC and MRTF-MADS comprise a novel tumor suppression pathway that is essential for hematopoiesis. Apcmin/Diaph1-deficient mice may prove to be a useful pre-clinical model for the development of more effective theranostic tools to attack MDS. Citation Format: Julie D. Turner, Susan M. Kitchen-Goosen, Andrew M. Howard, Heather L. Schumacher, Arthur S. Alberts. APC and DIAPH1 collaborate to suppress myelodysplastic syndrome (MDS) pathogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4194. doi:10.1158/1538-7445.AM2015-4194