STAT3 supports experimental K-RasG12D-induced murine myeloproliferative neoplasms dependent on serine phosphorylation (#63)
Juvenile Myelomonocytic Leukemia (JMML), Acute
Myeloid Leukemia (AML) and other myeloproliferative neoplasms (MPN) are
genetically heterogeneous but frequently display activating mutations in Ras GTPases
and expression of Signal Transducer and Activator of Transcription 3 (STAT3). Altered
STAT3 activity is observed in up to 50% of AML correlating with poor prognosis.
Activated STAT proteins, classically associated with tyrosine phosphorylation, support
tumor development as transcription factors, but alternative STAT functions
independent of tyrosine phosphorylation have been documented, including a role
for serine phosphorylated STAT3 in mitochondria supporting transformation by N-
and K-Ras. We examined the
requirement for STAT3 in experimental K-Ras-dependent hematopoietic neoplasia in
mice. We show that STAT3 is phosphorylated on S727 but not Y705 in diseased
animals. Moreover, a mouse with a point mutation abrogating STAT3 S727 phosphorylation
displayed delayed onset and decreased disease severity with significantly
extended survival. Activated K-Ras required STAT3 for cytokine-independent
growth of myeloid progenitors in vitro, and mitochondrially restricted STAT3
and STAT3-Y705F, both transcriptionally inert mutants, supported
factor-independent growth. STAT3 was dispensable for growth of normal or
K-Ras-mutant myeloid progenitors in response to cytokine stimulation. However,
abrogation of STAT3-S727 phosphorylation impaired factor-independent malignant
growth. These data document that serine phosphorylated mitochondrial STAT3 supports
neoplastic hematopoietic cell growth induced by K-Ras.