Expression Profiling of a Hemopoietic Cell Survival Transcriptome Identifies a Functional Prognostic Gene Signature in Normal Karyotype AML.

Abstract 1618

Poster Board I-644

Deregulated cell survival programs are a classical hallmark of cancer. We have previously identified a serine residue (Ser585) in the cytoplasmic domain of the bc subunit of the granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3) receptors that selectively and independently promotes hemopoietic cell survival. We now show that Ser585 phosphorylation is constitutive in the majority of acute myeloid leukemia (AML) patient samples indicating that this hemopoietic “survival-only” pathway is frequently deregulated in leukemia. This constitutive Ser585 phosphorylation is refractory to tyrosine kinase inhibitors allowing the survival of a quiescent population of leukemic progenitor cells in vitro. We performed a global expression screen to identify gene targets of this survival-only pathway and report a unique bc Ser585-regulated transcriptome. Pathway analysis defines a gene network enriched for PI 3-kinase target genes as well as a cluster of genes involved in cancer and cell survival. From this panel of Ser585-regulated genes, we have validated by Q-RT-PCR a “six-gene Ser585-signature” that is deregulated in AML blasts exhibiting constitutive Ser585 phosphorylation. We show that siRNA-mediated knockdown of key components of this Ser585-signature induces apoptosis in CD34⁺CD38^-CD123⁺ leukemic stem and progenitor cells. Furthermore, multivariate analysis indicates that the Ser585-signature is an independent prognostic indicator of overall patient survival in normal karyotype AML (n=56, HR=2.0, p=0.01). These results delineate a novel cytokine-regulated Ser585/PI3-kinase signalling network that is deregulated in AML and identify new prognostic targets with therapeutic potential.