Poster Presentation 25th Lorne Cancer Conference 2013

Mitochondrial-STAT3 supports K-Ras induced myeloproliferative disease in vivo. (#190)

Daniel J Gough 1 , David E Levy 2
  1. Monash Institute of Medical Research, Clayton, Vic, Australia
  2. Experimental Pathology, New York University, New York, NY, USA
Acute Myeloid Leukemia (AML) is a disease characterized by the aberrant expansion of white blood cells leading to death from infection, hemorrhage or organ infiltration. AML is genetically heterogeneous, however, activating mutations in the RasGTPases (typically K- or N-Ras) are found in 15-44% of AML. Likewise, the sustained activation or over-expression of signal transducer and activator of transcription 3 (STAT3) is a common event in AML (up to 50% of cases) and correlates with poor therapeutic responses. The current dogma suggests that STAT3 is constitutively tyrosine phosphorylated leading to sustained transcription of STAT3 target genes which provide a proliferative and survival advantage to transformed cells. This paradigm is important, but needs to be amended to address the recent discovery of non-canonical, mitochondrial activity of STAT3. We found that STAT3 is phosphorylated on S727 which is necessary for mitochondrial activity, but not on Y705 which is required for transcriptional activity in a potent mouse model of K-Ras driven myeloproliferative disease (MPD). Moreover, mutation of S727 in STAT3 decreases KRasG12D driven MPD onset, severity and significantly extends survival in vivo. To differentiate between the nuclear and mitochondrial activities of STAT3 we engineered KRasG12D, STAT3-/- bone marrow progenitor cells to express wild-type STAT3, STAT3Y705F or a mitochondrially-restricted STAT3 mutant. The expression of each of these STAT3 variants were similarly capable of rescuing growth factor independent myeloid colony formation in colony formation unit assays. Together these data confirm that the mitochondrial pool of STAT3 is important for K-RasG12D driven AML in vivo.