BCR–ABL promotes neutrophil differentiation in the chronic phase of chronic myeloid leukemia by downregulating c-Jun expression

Kobayashi, Susumu; Kimura, Fumihiko; Ikeda, Takashi; Osawa, Yukiko; Torikai, Hiroki; Kobayashi, Ayako; Sato, Ken; Motoyoshi, Kazuo

doi:10.1038/leu.2009.74

Cited by 18 publications

(12 citation statements)

References 38 publications

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“…It has been reported that the constitutively active tyrosine kinase BCR-ABL promotes neutrophil differentiation by downregulating c-Jun expression, while BCR-ABL inhibition by imatinib promotes monocytic differentiation in KCL22/α cells. 48 Our previous work has also indicated that BCR-ABL may have an indirect effect on OA by promoting granulocytic differentiation. 21 In addition, PPARγ is required for terminal maturation in the granulocytic lineage in vitro , but to a lesser extent for the early stages of hematopoietic cell development.…”

Section: Discussionmentioning

confidence: 95%

Increased peroxisome proliferator-activated receptor γ activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells

et al. 2017

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Imatinib is actively transported by organic cation transporter-1 (OCT-1) influx transporter, and low OCT-1 activity in diagnostic chronic myeloid leukemia blood mononuclear cells is significantly associated with poor molecular response to imatinib. Herein we report that, in diagnostic chronic myeloid leukemia mononuclear cells and BCR-ABL1+ cell lines, peroxisome proliferator-activated receptor γ agonists (GW1929, rosiglitazone, pioglitazone) significantly decrease OCT-1 activity; conversely, peroxisome proliferator-activated receptor γ antagonists (GW9662, T0070907) increase OCT-1 activity. Importantly, these effects can lead to corresponding changes in sensitivity to BCR-ABL kinase inhibition. Results were confirmed in peroxisome proliferator-activated receptor γ-transduced K562 cells. Furthermore, we identified a strong negative correlation between OCT-1 activity and peroxisome proliferator-activated receptor γ transcriptional activity in diagnostic chronic myeloid leukemia patients (n=84; P<0.0001), suggesting that peroxisome proliferator-activated receptor γ activation has a negative impact on the intracellular uptake of imatinib and consequent BCR-ABL kinase inhibition. The inter-patient variability of peroxisome proliferator-activated receptor γ activation likely accounts for the heterogeneity observed in patient OCT-1 activity at diagnosis. Recently, the peroxisome proliferator-activated receptor γ agonist pioglitazone was reported to act synergistically with imatinib, targeting the residual chronic myeloid leukemia stem cell pool. Our findings suggest that peroxisome proliferator-activated receptor γ ligands have differential effects on circulating mononuclear cells compared to stem cells. Since the effect of peroxisome proliferator-activated receptor γ activation on imatinib uptake in mononuclear cells may counteract the clinical benefit of this activation in stem cells, caution should be applied when combining these therapies, especially in patients with high peroxisome proliferator-activated receptor γ transcriptional activity.

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Section: Discussionmentioning

confidence: 95%

Increased peroxisome proliferator-activated receptor γ activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells

et al. 2017

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“…Remarkably, even though ABL1 did not affect myeloid differentiation of HSCs, 5,6 and BCR-ABL1 seemed to promote myeloid differentiation, 26 loss of ABL1 in BCR-ABL1 leukemic cells resulted in dramatic arrest of myeloid differentiation. Similarly, although ABL1 does not regulate the number of HSCs, BCR-ABL1 promotes rather mild expansion of LSCs in CML-CP 4,66 (and present study); nonetheless, rapid expansion of LSCs was observed in the absence of ABL1.…”

Section: /2mentioning

confidence: 91%

“…26,27 Although all moribund mice injected with BCR-ABL1 cells developed splenomegaly (supplemental Figure 3 inhibited (Klf1, Lmo2, Il3, Pml, Tesc, Vegfa, and Zfp36) whereas 5 genes associated with differentiation arrest were preferentially expressed (Bcl6, Lyn, Id2, Inpp5d, and Kit) ( Figure 4D). …”

Section: Abl1 Promotes Myeloid Differentiation Of Bcr-abl1-positive Lmentioning

confidence: 99%

Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases

Dasgupta

Koptyra

Hoser

et al. 2016

Blood

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“…Using two in vivo inflammation models, we showed that the abrogation of AKT1 markedly promotes the acute inflammatory injuries and potentiates the neutrophil bactericidal capacities, indicating a critical role for AKT1 in regulating neutrophil-mediated acute inflammation. Emerging evidence suggests a role for PI3K/AKT signaling in the regulation of acute and chronic inflammatory processes (14,(40)(41)(42)(43)(44). These findings led to the prospect of considering PI3K or AKT isoforms as promising drug targets for the modulation of inflammatory and autoimmune disorders, cancer, and transplantation (14).…”

Section: Discussionmentioning

confidence: 99%

Kinase AKT1 Negatively Controls Neutrophil Recruitment and Function in Mice

Liu

Wang

et al. 2013

The Journal of Immunology

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Neutrophils are critically involved in host defense and inflammatory injury. However, intrinsic signaling mechanisms controlling neutrophil recruitment and activities are poorly defined. In this article, we showed that protein kinase AKT1 (also known as PKBα) is the dominant isoform expressed in neutrophils and is downregulated upon bacterial infection and neutrophil activation. AKT1 deficiency resulted in severe disease progression accompanied by recruitment of neutrophils and enhanced bactericidal activity in the acute inflammatory lung injury (ALI) and the Staphylococcus aureus infection mouse models. Moreover, the depletion of neutrophils efficiently reversed the aggravated inflammatory response, but adoptive transfer of AKT1−/− neutrophils could potentiate the inflammatory immunity, indicating an intrinsic effect of the neutrophil in modulating inflammation in AKT1−/− mice. In the ALI model, the infiltration of neutrophils into the inflammatory site was associated with enhanced migration capacity, whereas inflammatory stimuli could promote neutrophil apoptosis. In accordance with these findings, neutralization of CXCR2 attenuated neutrophil infiltration and delayed the occurrence of inflammation. Finally, the enhanced bactericidal activity and inflammatory immunity of AKT-deficient neutrophils were mediated by a STAT1-dependent, but not a mammalian target of rapamycin–dependent, pathway. Thus, our findings indicated that the AKT1–STAT1 signaling axis negatively regulates neutrophil recruitment and activation in ALI and S. aureus infection in mice.

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BCR–ABL promotes neutrophil differentiation in the chronic phase of chronic myeloid leukemia by downregulating c-Jun expression

Cited by 18 publications

References 38 publications

Increased peroxisome proliferator-activated receptor γ activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells

Increased peroxisome proliferator-activated receptor γ activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells

Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases

Kinase AKT1 Negatively Controls Neutrophil Recruitment and Function in Mice

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