STAT5-dependent regulation of CDC25A by miR-16 controls proliferation and differentiation in FLT3-ITD acute myeloid leukemia

Sueur, Gabrielle; Boutet, Alison; Gotanègre, Mathilde; Mas, Véronique Mansat‐De; Besson, Arnaud; Manenti, Stéphane; Bertoli, Sarah

doi:10.1038/s41598-020-58651-x

Cited by 8 publications

(2 citation statements)

References 43 publications

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“…AML-specific Flt3 mutations have induced STAT target genes (Mizuki et al, 2003) and FLT3-D835 mutation has led to constitutive activation of STAT5 (Taketani et al, 2004). Levels of CDC25A, a phosphatase important for proliferation and differentiation in AML expressing the FLT3-ITD mutation, are controlled by a complex STAT5/miR-16 transcription and translation pathway, confirming that FLT3-ITD/STAT5/miR-16/CDC25A interplay is important for AML cell proliferation and differentiation (Sueur et al, 2020). Furthermore, induced inflammatory response in the human AML niche leads to increased activity of the JAK/STAT pathway in AML blasts and BM stromal cells promoting leukemic proliferation (Habbel et al, 2020).…”

Section: Jak-stat In Hematologic Malignanciesmentioning

confidence: 86%

JAK-STAT in Early Hematopoiesis and Leukemia

Fasouli

Katsantoni

2021

Front. Cell Dev. Biol.

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Hematopoietic stem cells (HSCs) produce all the terminally differentiated blood cells and are controlled by extracellular signals from the microenvironment, the bone marrow (BM) niche, as well as intrinsic cell signals. Intrinsic signals include the tightly controlled action of signaling pathways, as the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Activation of JAK-STAT leads to phosphorylation of members of the STAT family to regulate proliferation, survival, and self-renewal of HSCs. Mutations in components of the JAK-STAT pathway are linked with defects in HSCs and hematologic malignancies. Accumulating mutations in HSCs and aging contribute to leukemia transformation. Here an overview of hematopoiesis, and the role of the JAK-STAT pathway in HSCs and in the promotion of leukemic transformation is presented. Therapeutic targeting of JAK-STAT and clinical implications of the existing research findings are also discussed.

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Section: Jak-stat In Hematologic Malignanciesmentioning

confidence: 86%

JAK-STAT in Early Hematopoiesis and Leukemia

Fasouli

Katsantoni

2021

Front. Cell Dev. Biol.

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“…Stronger phosphorylation signals were found in FLT3-ITD-mutated AML patients with higher ITD lengths [29]. Aberrant cell-death signaling through receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and upregulation of anti-apoptotic myeloid cell leukemia-1 (MCL-1), aberrant cell-cycle regulation, among others through CDC25A and CDC25C, and aberrant oncogenic signaling through phosphorylation of cytokine receptor common subunit beta (CSF2RB) were detected in FLT3-ITD-mutated cells [30][31][32][33][34][35]. Furthermore, FLT3-ITD mediates metabolic effects leading to the upregulation of aerobic glycolysis and cell-extrinsic effects by affecting dendritic cells and T cells [36,37].…”

Section: Signaling Of Flt3 and Flt3-itdmentioning

confidence: 99%

How ITD Insertion Sites Orchestrate the Biology and Disease of FLT3-ITD-Mutated Acute Myeloid Leukemia

Haage

Schraven

Mougiakakos

et al. 2023

Cancers

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Mutations of the FLT3 gene are among the most common genetic aberrations detected in AML and occur mainly as internal tandem duplications (FLT3-ITD). However, the specific sites of FLT3-ITD insertion within FLT3 show marked heterogeneity regarding both biological and clinical features. In contrast to the common assumption that ITD insertion sites (IS) are restricted to the juxtamembrane domain (JMD) of FLT3, 30% of FLT3-ITD mutations insert at the non-JMD level, thereby integrating into various segments of the tyrosine kinase subdomain 1 (TKD1). ITDs inserted within TKD1 have been shown to be associated with inferior complete remission rates as well as shorter relapse-free and overall survival. Furthermore, resistance to chemotherapy and tyrosine kinase inhibition (TKI) is linked to non-JMD IS. Although FLT3-ITD mutations in general are already recognized as a negative prognostic marker in currently used risk stratification guidelines, the even worse prognostic impact of non-JMD-inserting FLT3-ITD has not yet been particularly considered. Recently, the molecular and biological assessment of TKI resistance highlighted the pivotal role of activated WEE1 kinase in non-JMD-inserting ITDs. Overcoming therapy resistance in non-JMD FLT3-ITD-mutated AML may lead to more effective genotype- and patient-specific treatment approaches.

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Age‐associated myeloid malignancies – the role of STAT3 and STAT5 in myelodysplastic syndrome and acute myeloid leukemia

Fasouli,

Katsantoni

2024

FEBS Letters

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In the last few decades, the increasing human life expectancy has led to the inflation of the elderly population and consequently the escalation of age‐related disorders. Biological aging has been associated with the accumulation of somatic mutations in the Hematopoietic Stem Cell (HSC) compartment, providing a fitness advantage to the HSCs leading to clonal hematopoiesis, that includes non‐malignant and malignant conditions (i.e. Clonal Hematopoiesis of Indeterminate Potential, Myelodysplastic Syndrome and Acute Myeloid Leukemia). The Janus Kinase‐Signal Transducer and Activator of Transcription (JAK–STAT) pathway is a key player in both normal and malignant hematopoiesis. STATs, particularly STAT3 and STAT5, are greatly implicated in normal hematopoiesis, immunity, inflammation, leukemia, and aging. Here, the pleiotropic functions of JAK–STAT pathway in age‐associated hematopoietic defects and of STAT3 and STAT5 in normal hematopoiesis, leukemia, and inflammaging are reviewed. Even though great progress has been made in deciphering the role of STATs, further research is required to provide a deeper understanding of the molecular mechanisms of leukemogenesis, as well as novel biomarkers and therapeutic targets for improved management of age‐related disorders.

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STAT5-dependent regulation of CDC25A by miR-16 controls proliferation and differentiation in FLT3-ITD acute myeloid leukemia

Cited by 8 publications

References 43 publications

JAK-STAT in Early Hematopoiesis and Leukemia

JAK-STAT in Early Hematopoiesis and Leukemia

How ITD Insertion Sites Orchestrate the Biology and Disease of FLT3-ITD-Mutated Acute Myeloid Leukemia

Age‐associated myeloid malignancies – the role of STAT3 and STAT5 in myelodysplastic syndrome and acute myeloid leukemia

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