FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD–specific STAT5 activation

Yoshimoto, Goichi; Miyamoto, Toshihiro; Jabbarzadeh-Tabrizi, Siamak; Iino, Tadafumi; Rocnik, Jennifer L.; Kikushige, Yoshikane; Mori, Yasuo; Shima, Takahiro; Iwasaki, Hiromi; Takenaka, Katsuto; Nagafuji, Koji; Mizuno, Shin Ichi; Niiro, Hiroaki; Gilliland, Gary; Akashi, Koichi

doi:10.1182/blood-2008-12-196055

Cited by 214 publications

(197 citation statements)

References 57 publications

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“…35,36 FLT3 ITD has been shown to stimulate MCL1 expression in HSCs and LICs via the STAT5-dependent signaling pathway. 37 Finally, the expression of genes involved in transformation and survival (Rgs2, Mycn, Myc and Mcl1; Figure 4f) were strongly upregulated, indicating a deregulated GMP population that has partially or fully left the myeloid differentiation path and acquired HSC-like self-renewal and enhanced survival.…”

Section: Resultsmentioning

confidence: 98%

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

et al. 2012

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Biallelic CEBPA mutations and FMS-like tyrosine kinase receptor 3 (FLT3) length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear because of a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of an internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed CCAAT/enhancer binding protein alpha (C/EBPa) mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMPs) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPa mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations, we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.

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Section: Resultsmentioning

confidence: 98%

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

et al. 2012

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“…Others have found that cytokines secreted by bone marrow stromal cells protect JAK2-mutated cells from the effects of a JAK2 inhibitor (Manshouri et al, 2011), and exogenous IL3 is known to protect FLT3 mutated cells from a panel of FLT3 inhibitors including lestaurtinib, sorafenib and sunitinib (Pratz et al, 2010). STAT5 phosphorylation drives MCL1 expression in AML (Yoshimoto et al, 2009), and therefore by-passing niche-induced, STAT5-driven MCL1 up-regulation via transcriptional CDK inhibition may be an important strategy against chemoresistant AML in the bone marrow niche, bearing in mind that cytokine-driven STAT5 phosphorylation is a feature of clones from chemoresistant patients in AML (Rosen et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Finally we established a response mechanism in primary patient samples involving inactivation of RP2 and depletion of MCL1. MCL1 can additionally be regulated through FLT3 and STAT5, especially in haematopoietic stem cells and leukaemic CD34 + CD38 À cells (Yoshimoto et al, 2009), so we also investigated the contribution of this pathway to the action of TG02 in this treatment-resistant cell population. , 2 mmol/l l-glutamine, 100 u/ml penicillin and 10 lg/ ml streptomycin).…”

Section: Summmarymentioning

confidence: 99%

The multi‐kinase inhibitor TG02 overcomes signalling activation by survival factors to deplete MCL1 and XIAP and induce cell death in primary acute myeloid leukaemia cells

et al. 2012

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SummmaryThe novel multi-kinase inhibitor TG02 has selectivity against cell cycle and transcriptional cyclin dependent kinases (CDKs) as well as fms-like tyrosine kinase receptor-3 (FLT3). Inhibition of transcriptional CDKs preferentially depletes short-lived proteins such as MCL1. We evaluated the in vitro toxicity of TG02 to primary acute myeloid leukaemia (AML) cells in the presence of survival signalling pathway activation by cytokines and fibronectin. One hundred nanomolar TG02 induced a median decrease of 40% in bulk cell survival and 43% in the CD34 + CD38 À CD123 + subset. A 90% inhibitory concentration of 500 nmol/l indicated that TG02 toxicity is not halted by protective cell cycle arrest. Samples with FLT3 internal tandem duplication were not preferentially targeted. By flow cytometry, TG02 treatment caused loss of RNA Polymerase II serine 2 phosphorylation in patient samples, which correlated strongly with BAX activation (R 2 =0Á89), suggesting these as potential biomarkers for clinical studies. MCL1 and XIAP expression also decreased. Repeated brief exposure to TG02 in MOLM-13 cells did not result in compensatory up-regulation of survival protein expression. In conclusion, TG02 is potently cytotoxic towards CD34 + CD38À CD123 + and bulk AML cells, despite protective signalling pathway activation. This antitumour activity is most likely mediated by dephosphorylation of RNA Polymerase II leading to depletion of survival molecules such as MCL1 and XIAP, with subsequent BAX activation and apoptosis.

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“…Activated STAT-5 up-regulates MCL-1 (myeloid cell leukemia-1), which is an essential survival factor for both normal and leukemic hematopoiesis. STAT-5 inhibition then completely abrogates this process 40 . Futhermore, in chronic myeloid leukemia, the BCR-ABL kinase activity also activates STAT-5 and causes IL-3 independent expression of antiapoptotic protein Bcl-X L (ref.…”

Section: Cytokines In Aml Proliferation and Prognosismentioning

confidence: 99%

The role of cytokines in acute myeloid leukemia: A systematic review

Kupsa¹,

Horáček²,

Jebavý³

2012

BIOMED PAP

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Background. Acute myeloid leukemia (AML) shows a high degree of heterogeneity owing to a variety of mutations and the mechanisms of leukemogenesis. This heterogeneity is often not reflected in standard treatment approaches which while providing predictable outcomes in the majority of patients fail in particular cases even with high-dose multiagent chemotherapy regimens. Further, the unselective effect of chemotherapy leads to high treatment-related toxicity and the enormous risk of infection during prolonged pancytopenia, preventing further dose escalation. Objectives. Cytokines play a role in leukemogenesis, AML cell persistence and treatment outcome. In this review we highlight cytokine dependent mechanisms essential for AML cell survival and the role of single cytokines in leukemogenesis and allogeneic transplantation-related phenomena. Cytokine-related mechanisms of leukemogenesis, AML cell persistence and resistance to chemotherapy are complex. Modulation of the cytokine network can disrupt signalling pathway activation and overcome the high resistance to treatment. It may also increase the selectivity of AML treatment, reduce the overall treatment-related toxicity and improve outcomes of AML treatment in all age groups of patients. Conclusions. This review provides a deeper insight into these processes with focus on the most vulnerable step. Special attention is paid to the possibility of selective influence on defined cell populations for therapeutic target. We believe that modulating cytokine-dependent processes in AML is an approach that could be included in standard chemotherapeutic regimens for improving overall treatment outcome.

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FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD–specific STAT5 activation

Cited by 214 publications

References 57 publications

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

The multi‐kinase inhibitor TG02 overcomes signalling activation by survival factors to deplete MCL1 and XIAP and induce cell death in primary acute myeloid leukaemia cells

The role of cytokines in acute myeloid leukemia: A systematic review

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