FACS analysis of Stat3/5 signaling reveals sensitivity to G-CSF and IL-6 as a significant prognostic factor in pediatric AML: a Children's Oncology Group report

Redell, Michele S.; Ruiz, Marcos J.; Gerbing, Robert B.; Alonzo, Todd A.; Lange, Beverly J.; Tweardy, David J.; Meshinchi, Soheil

doi:10.1182/blood-2012-04-421925

Cited by 36 publications

(42 citation statements)

References 28 publications

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“…Multivariate analysis confirmed the independent prognostic power of the pretreatment Stat3/5 signaling biosignature for EFS (P ¼ 0.017), whereas heavy transfusion requirements was the other independent prognostic factor for both OS (P ¼ 0.004) and EFS (P ¼ 0.029, Supplementary Tables S1 and S2). These findings are in line with prior observations in AML (12,27), and strongly suggest involvement of aberrant signaling via Stat3/5 in MDS pathobiology. We further performed unsupervised clustering of patient and nonclonal samples ( Supplementary Fig.…”

Section: Resultssupporting

confidence: 82%

“…In both adult and pediatric AML, functional phenotyping of Stat3/5 signaling networks by phospho-protein flow cytometry provides important prognostic information and pathobiologic insights (12,27,37). Yet, despite the reciprocal interactions of DNA methylation with Stat3/5 signaling (19,29,38), the high rate of mutations (39) and aberrant methylation of genes involved in cell signaling (18) in high risk MDS, no current study addresses the Stat3/5 signaling alterations at the single HSPC level in such patients.…”

Section: Discussionmentioning

confidence: 99%

“…Myeloid blasts display variable expression of CSF3R and a heterogeneous response to G-CSF stimulation (12,27,35). Surface CSF3R could not be assessed concomitantly in the DP and DN subsets of G-CSF-stimulated CD34 þ blasts because it is downregulated after G-CSF ligation (36).…”

Section: Ipss-r Cytogenetics Ipss Cytogenetics Responsementioning

confidence: 99%

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The Stat3/5 Signaling Biosignature in Hematopoietic Stem/Progenitor Cells Predicts Response and Outcome in Myelodysplastic Syndrome Patients Treated with Azacitidine

Miltiades

Lamprianidou

Vassilakopoulos

et al. 2016

Clinical Cancer Research

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and independently predicted event-free survival. We further identified a CD34 þ G-CSF-inducible Stat3/5 double-positive subpopulation (DP subset) whose pretreatment levels were inversely associated with treatment response and cytogenetics. The kinetics of the DP subset followed the response to azacitidine and the disease course, whereas its molecular characteristics and cellular hierarchy were consistent with a leukemia propagating cell phenotype. Conclusions: Our findings provide a novel link among Stat3/5 signaling and MDS pathobiology and suggest that the Stat3/5 signaling biosignature may serve as both a response biomarker and treatment target.

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Section: Resultssupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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The Stat3/5 Signaling Biosignature in Hematopoietic Stem/Progenitor Cells Predicts Response and Outcome in Myelodysplastic Syndrome Patients Treated with Azacitidine

Miltiades

Lamprianidou

Vassilakopoulos

et al. 2016

Clinical Cancer Research

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“…Alexandra M. Stevens, 1 Marcos J. Ruiz, 1 Robert B. Gerbing, 2 Todd A. Alonzo, 3 Alan S. Gamis,4 and Michele S. Redell…”

mentioning

confidence: 99%

“…[1][2][3][4] STATs are critical signaling intermediates in hematopoietic cells and are activated by growth factors and cytokines in the bone marrow (BM), including granulocyte-colony stimulating factor (G-CSF) and interleukin-6 (IL-6). G-CSF stimulation results in phosphorylation of STAT3 and STAT5.…”

mentioning

confidence: 99%

Ligand-induced STAT3 signaling increases at relapse and is associated with outcome in pediatric acute myeloid leukemia: a report from the Children's Oncology Group

et al. 2015

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Phosflow assessment of PDGFRA phosphorylation state: A guide for tyrosine kinase inhibitor targeted therapy in hypereosinophilia patients

et al. 2021

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Clonal eosinophilia is a hematologic disorder caused by translocation in growth factor receptor (GFR) genes. Despite the identified molecular mechanisms underlying clonal hypereosinophilia, the distinction between clonal and reactive eosinophilia has remained challenging due to the diversity of partner genes for translocated GFRs. This study aimed to examine the feasibility of phosphoflow cytometry in the diagnosis of clonal hypereosinophilia through evaluating the level of platelet‐derived growth factor receptor alpha (PDGFRA) phosphorylation and its correlation with PDGFRA genetic aberration. Blood samples were collected from 45 hypereosinophilia patients and 10 healthy controls. Using phosphoflow cytometry method, the phosphorylation state of PDGFRA was assessed. The specificity of phosflow results was confirmed by western blotting and eventually compared with qRT‐PCR expression analysis of 3′‐region of PDGFRA. To detect the genetic aberration of PDGFRA, 5′‐rapid amplification of cDNA ends (5′‐RACE) was performed. Phosflow analysis illustrated that 9 of 45 hypereosinophilic patients had higher level of PDGFRA phosphorylation while sequence analysis of 5′‐RACE‐PCR fragments confirmed that in seven cases of them, there was a PDGFRA‐FIP1L1 fusion. We also verified that two of nine patients with hyperposphorylated PDGFRA hold ETV6‐PDGFRA and STRN‐PDGFRA rearrangements. Importantly, nine cases also had significantly higher levels of PDGFRA mRNA expression when compared with healthy controls, and cases with no PDGFRA rearrangement. These findings highlight a robust correlation between hyperphosphorylation state of PDGFRA and aberrant PDGFRA gene fusions. This implicates phosflow as an efficient and reliable technique raising an intriguing possibility that it could replace other genomic and cDNA‐amplification‐based diagnostic approaches with limited effectiveness.

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FACS analysis of Stat3/5 signaling reveals sensitivity to G-CSF and IL-6 as a significant prognostic factor in pediatric AML: a Children's Oncology Group report

Abstract: Key Points• In pediatric AML, patterns of Stat3 activation by G-CSF and IL-6 can be identified that are associated with survival.• Such functional information may be useful for risk assessment and for determining which patients may benefit from alternative therapies.

Cited by 36 publications

References 28 publications

The Stat3/5 Signaling Biosignature in Hematopoietic Stem/Progenitor Cells Predicts Response and Outcome in Myelodysplastic Syndrome Patients Treated with Azacitidine

The Stat3/5 Signaling Biosignature in Hematopoietic Stem/Progenitor Cells Predicts Response and Outcome in Myelodysplastic Syndrome Patients Treated with Azacitidine

Ligand-induced STAT3 signaling increases at relapse and is associated with outcome in pediatric acute myeloid leukemia: a report from the Children's Oncology Group

Phosflow assessment of PDGFRA phosphorylation state: A guide for tyrosine kinase inhibitor targeted therapy in hypereosinophilia patients

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