Interleukin 4 induces apoptosis of acute myeloid leukemia cells in a Stat6-dependent manner

Background Acute myeloid leukemia (AML) is one of the most common hematological diseases in adults. The overall survival rate remains unsatisfactory. It is urgent to identify potential prognostic biomarkers and develop new molecular therapeutic strategies for AML. Signal transducer and activator of transcription (STAT) is a family of genes that encode intracellular transcription factors. STATs are associated with leukemogenesis, cellular transformation, and cell cycle in AML. Methods We used sequencing data and clinical data from The Cancer Genome Atlas (TCGA) and ONCOMINE to identify expression difference, gene variability and correlation as well as prognostic effects of STAT genes in AML patients. Then, we verified the expression difference of STAT6 between healthy control and AML patients and its prognostic impact in Gene Expression Omnibus (GEO) database and our own recruited cohort. Results The mRNA level of STAT6 was increased in AML patients among TCGA, GEO and ONCOMINE public datasets and was found to be an independent risk factor of overall survival in all AML patients and patients who only received chemotherapy by multivariate analysis. In our study, STAT6 mRNA level was markedly up-regulated in AML patients (n=105) compared to healthy donor (n=39) (P=0.0435) as a validated cohort. Patients that only received chemotherapy in high STAT6 group showed significantly lower overall survival (OS) (P=0.0055). Conclusion STAT6 expression was increased in AML patients. STAT6 was found to be an adverse prognosis factor in AML patients, especially those who only received chemotherapy treatments.

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“… 21 , 22 STAT6 induced by interleukin 4 (IL-4) also has an anti-leukemia effect in primitive AML cells. 23 …”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of STAT6 as a Prognostic and Predictive Biomarker in Acute Myeloid Leukemia

Liu

Zhu

Yan

et al. 2020

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“…Mononuclear cells were isolated from primary samples using density gradient centrifugation (Ficoll-Hypaque; density 1.077 g/mL, Sigma-Aldrich) within 24 h from harvesting. Cells were then either cryopreserved in liquid nitrogen in the presence of 90% fetal bovine serum (FBS) (Biovest) and 10% DMSO, or cultured at a density 1 × 10 6 /mL in S7 medium (83% IMDM, 15% BIT, 500 nM SR1, 500 nM UM729 (all from StemCell Technologies), 100 ng/ml SCF, 20 ng/ml G-CSF, 50 ng/ml FLT3-L, 20 ng/ml IL-3 (R&D), 0.1 mM β-Mercaptoethanol, 1% penicillin/streptomycin, 1% GlutaMAX 1% (Lonza)) 49 , or RPMI-1640 medium (Lonza) containing 10% heat-inactivated FBS, 2mM L-glutamine, 10 mM HEPES, and 100 U/mL of penicillin/streptomycin, at a density 1 × 10 6 /mL.…”

Section: Methodsmentioning

confidence: 99%

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

et al. 2020

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Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38−CD123+ and CD34+CD38−CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials.

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“…For the ex vivo transplantation assay, serially propagated dsRed + KMT2A-MLLT3 leukemia cells 44 were used 69 . Briefly, 5000 freshly isolated CD117 + quaternary transplant leukemia cells were treated ex vivo with or without 500 ng/ml MIF (Peprotech) in StemSpan™ SFEM (Stemcell Technologies) for 3 days before transplantation into sublethally irradiated (600 cGy) recipients.…”

Section: Methodsmentioning

confidence: 99%

De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia

et al. 2018

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Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3ITD, FLT3N676K, and NRASG12D accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3N676K mutations accelerate disease, possibly by providing stimulatory factors. Herein, we show that one such factor, MIF, promotes survival of mouse KMT2A-MLLT3 leukemia initiating cells. We identify acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 in KMT2A-MLLT3 leukemia cells that favored clonal expansion. During clonal evolution, we observe serial genetic changes at the KrasG12D locus, consistent with a strong selective advantage of additional KrasG12D. KMT2A-MLLT3 leukemias with signaling mutations enforce Myc and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlight the importance of activated signaling as a contributing driver.

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Interleukin 4 induces apoptosis of acute myeloid leukemia cells in a Stat6-dependent manner

Cited by 40 publications

References 42 publications

<p>Identification and Validation of <em>STAT6</em> as a Prognostic and Predictive Biomarker in Acute Myeloid Leukemia</p>

<p>Identification and Validation of <em>STAT6</em> as a Prognostic and Predictive Biomarker in Acute Myeloid Leukemia</p>

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia

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