Aberrantly low STAT3 and STAT5 responses are associated with poor outcome and an inflammatory gene expression signature in pediatric acute myeloid leukemia

Abstract

The relapse rate for children with acute myeloid leukemia is nearly 40% despite aggressive chemotherapy and often stem cell transplant. We sought to understand how environment-induced signaling responses are associated with clinical response to treatment. We previously reported that patients whose AML cells showed low G-CSF-induced STAT3 activation had inferior event-free survival compared to patients with stronger STAT3 responses. Here, we expanded the paradigm to evaluate multiple signaling parameters induced by a more physiological stimulus. We measured STAT3, STAT5 and ERK1/2 responses to G-CSF and to stromal cell-conditioned medium for 113 patients enrolled on COG trials AAML03P1 and AAML0531. Low inducible STAT3 activity was independently associated with inferior event-free survival in multivariate analyses. For inducible STAT5 activity, those with the lowest and highest responses had inferior event-free survival, compared to patients with intermediate STAT5 responses. Using existing RNA-sequencing data, we compared gene expression profiles for patients with low inducible STAT3/5 activation with those for patients with higher inducible STAT3/5 signaling. Genes encoding hematopoietic factors and mitochondrial respiratory chain subunits were overexpressed in the low STAT3/5 response groups, implicating inflammatory and metabolic pathways as potential mechanisms of chemotherapy resistance. We validated the prognostic relevance of individual genes from the low STAT3/5 response signature in a large independent cohort of pediatric AML patients. These findings provide novel insights into interactions between AML cells and the microenvironment that are associated with treatment failure and could be targeted for therapeutic interventions.

A novel function of STAT3β in suppressing interferon response improves outcome in acute myeloid leukemia

“…These findings indicate that STAT3β is pivotal for a G-CSF-induced myeloid differentiation program in AML blasts. As we did not observe alterations in G-CSF receptor ( Csf3r ) mRNA expression or in proliferation upon G-CSF stimulation, we assume that the absence of STAT3β does not affect receptor expression per se, but rather impairs endosomal recycling of the receptor causing reduced signaling, as previously suggested [ 46 – 48 ]. However, to obtain more detailed mechanistic insights further research is required.…”

“…In vivo, we also identified a reduction in myeloid lineage commitment in blasts lacking STAT3β, together with more rapid disease progression. Consistent with this, pediatric AML patient samples with low STAT3 phosphorylation upon G-CSF stimulation showed poorer OS than patients with a stronger STAT3 response [ 46 ].…”

High-Dimensional Mass Cytometry Analysis of Embryonic Antigens and Their Signaling Pathways in Myeloid Cells from Bone Marrow Aspirates in AML Patients at Diagnosis

“…The STAT3/5 signaling pathway is induced in leukemic blasts by environmental factors such as granulocyte colony-stimulating factor stimulation or interactions with stromal cells. Narayanan et al showed that AML patients with low environment-induced STAT3 pathway signaling had inferior outcomes compared to patients with a stronger inducible STAT3 response [23].…”

Signaling pathways governing the behaviors of leukemia stem cells

“…High expression of STAT3 is associated with shorter survival and poor clinical outcome in BMDSC, which is correlated with disease-initiating stem cells. 179 Inhibition of STAT3 by AZD9150, an antisense STAT3 inhibitor, decreased viability along with in vivo leukemic growth and induced LSCs' apoptosis. 180 Incorporation of AZD9150 with AML/MDS stem cells induced hematopoietic differentiation.…”