Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines

Hayakawa, Fumihiko; Towatari, Masayuki; Kiyoi, Hitoshi; Tanimoto, Mitsune; Kitamura, Toshio; Saito, Hidehiko; Naoe, Tomoki

doi:10.1038/sj.onc.1203354

Cited by 505 publications

(477 citation statements)

References 39 publications

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“…14 In accordance with previous data, the FLT3 ITD-related activation of STAT5 is a strong proliferative signal and probably the cause of expansion of the MPP compartment. 14,30,31 However, addition of FLT3 ITD in KLI cohorts had no effect on myeloid gene expression. Therefore, the higher frequency of myeloid progenitors can only be attributed to proliferative effect of FLT3 ITD.…”

Section: Resultsmentioning

confidence: 99%

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: 99%

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

et al. 2012

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“…(Wolf and Rohrschneider, 1999) Mutations in the FLT-3 gene constitutively activate Stat-5 and MAP-kinase pathways, promoting myeloid leukemia. (Hayakawa, et al, 2000, Nakao, et al, 1996 Multiple-Zf proteins, like FIZ1, feature prominently in networks that regulate gene expression, especially those that involve nuclear-receptors. FIZ1 is not homologous to any known Zf-families and we know little of its basic functions in the cell.…”

Section: Introductionmentioning

confidence: 99%

FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro

Mali

Zhang

Hoerauf

et al. 2007

Experimental Eye Research

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FIZ1 (Flt-3 Interacting Zinc-finger) interacts and co-purifies with the rod-specific transcription factor NRL (Neural Retina Leucine zipper). We hypothesize that FIZ1 is part of an interface between cell-specific factors, like NRL, and more ubiquitous regulatory networks that vary the absolute expression levels of some rod-specific genes (i.e. Rhodopsin). As part of an ongoing exploration of FIZ1's role in neural retina, in vivo, we have taken the first look at FIZ1 expression in the developing mouse retina during the retinal maturation period. Using the normal C57/B6 mouse as a model, multiple approaches were used including: immunoblotting, immunohistochemistry, and quantitative real-time PCR. Functional implications of FIZ1/NRL interaction, on NRL-and CRX-mediated activation of the Rhodopsin (Rho) and cGMPphosphodiesterase β-subunit gene (PDE6B) promoters, were examined by co-transfection assays. Immunoblot analysis revealed that FIZ1 protein levels were lowest in immature mouse neural retina (P0). FIZ1 concentration increased at least ten-fold as the neural retina matured to the adult state (P21 and later). Immunohistochemical comparison of immature post-natal and mature adult retina revealed increasing FIZ1 protein in photoreceptors, the inner plexiform layer, and the ganglion cell layer. Total retinal Fiz1 mRNA content increased as the neural retina matured. The expected increase in Rho mRNA level was also monitored as a genetic marker of photoreceptor maturation. In transient co-transfection assays of CV1 cells, FIZ1 synergized with NRL to activate transcription from the Rho and PDE6B gene promoters with some differences. In the case of the Rho promoter, FIZ1 synergized when both NRL and CRX were present. With the PDE6B promoter, FIZ1 synergized with NRL alone, and the inclusion of CRX decreased this synergy.Conclusions-These findings support previous evidence that FIZ1 is present in rodphotoreceptors. (Co-immunoprecipitation from nuclear-protein extracts with rod-specific NRL) FIZ1 expression increases in the neural retina during the retinal maturation period. Additionally, in vitro experiments demonstrate that FIZ1 has the potential to significantly increase the NRLmediated activation of photoreceptor-specific promoters. While CRX is not a strong activator of the PDE6B promoter, alone or with NRL, CRX decreased the synergy of NRL with FIZ1.

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“…These RTKs all share the same topology, consisting of five extracellular immunoglobulin-like domains, a juxtamembrane (JM) domain, a kinase domain interrupted by a kinase insertion domain, and an intracellular C-terminal domain [1]. Ligand binding to RTKs results in the activation of downstream effectors, including protein kinase B/Akt, signal transducers and activators of transcription (STATs) and extracellular signal-regulated kinases (ERKs) 1/2, leading to cell proliferation, differentiation and/or survival [2,3]. Recent studies have revealed that activating mutations of RTKs frequently occur in acute myelogenous leukemia (AML) patients.…”

Section: Introductionmentioning

confidence: 99%

MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells

et al. 2008

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Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines

Abstract: We have recently identi®ed an internal tandem duplication of the human Flt3 gene in approximately 20% of acute myeloid leukemia (AML) cases. In the present study, the wild-type and the mutant Flt3 genes were transfected into two IL-

Cited by 505 publications

References 39 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

FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro

MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells

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