Mammalian target of rapamycin inhibitor rapamycin enhances anti‐leukemia effect of imatinib on <scp>P</scp>h<b>+</b> acute lymphoblastic leukemia cells

Yang, Xi; He, Guangcui; Gong, Yuping; Zheng, Bohao; Shi, Fangfang; Shi, Rui; Xj, Yang

doi:10.1111/ejh.12202

Cited by 17 publications

(7 citation statements)

References 41 publications

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“…Cytofluorometric analysis of the apoptotic cell fraction was performed by measuring the uptake of Annexin V (KeyGEN biotech, Nanjing, China) and PI (Sigma-Aldrich Corporation, USA) according to the published protocol [27]. …”

Section: Methodsmentioning

confidence: 99%

High CFTR expression in philadelphia chromosome-positive acute leukemia protects and maintains continuous activation of BCR-ABL and related signaling pathways in combination with PP2A

et al. 2017

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Cystic fibrosis transmembrane conductance regulator (CFTR) is classified as an anion channel transporter of Cl− and HCO3−. Through interactions with its PDZ domain, CFTR is capable of regulating other proteins, such as protein phosphatase 2A (PP2A). The aberrant expression and mutation of CFTR have been observed in several tumor, but not in philadelphia chromosome–positive(Ph+) acute leukemia, including Ph+ B cell acute lymphoblastic leukemia(Ph+ B-ALL) and chronic myelogenous leukemia blast crisis phases (CML-BC). In this study, we demonstrated the mean expression level of CFTR in Ph+ acute leukemia cells was markedly higher than that in Ph- B-ALL and CML-chronic phase cells. CFTRinh-172, a classic CFTR inhibitor, down-regulated the expression of CFTR, p-BCR-ABL and classical Wnt/β-catenin signaling in Ph+ acute leukemia cells, while imatinib had no effect on CFTR. Importantly, reduced efficacy of CFTRinh-172 was closely associated with elevated PP2A phosphatase activity. Furthermore, we confirmed an interaction between CFTR and the PP2AA subunit in K562 cells. In addition, we demonstrated CFTR and PP2AA interact in the cytosol, resulting in PP2A complex inactivation and increased degradation of PP2A substrates via the lysosomal/proteasome pathway. In conclusion, our results showed CFTR was highly expressed in Ph+ acute leukemia, which protected and maintained the continuous activation of BCR-ABL and the canonical Wnt/β-catenin signaling pathway by decreasing PP2A phosphatase activity. According to this working model of the CFTR-PP2A-BCR-ABL axis, targeting the CFTR protein will activate PP2A and may offer a new treatment strategy for Ph+ acute leukemia, especially for patients exhibiting high levels of CFTR expression.

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Section: Methodsmentioning

confidence: 99%

High CFTR expression in philadelphia chromosome-positive acute leukemia protects and maintains continuous activation of BCR-ABL and related signaling pathways in combination with PP2A

et al. 2017

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“…Yang et al . showed that combining imatinib therapy with rapamycin overcame this effect and enabled induction of autophagy and cell cycle arrest in primary Ph+ B-ALL cells in vitro [138]. …”

Section: Mtor and B Cell Neoplasmsmentioning

confidence: 99%

Control of B lymphocyte development and functions by the mTOR signaling pathways

Iwata

Ramírez-Komo

Park

et al. 2017

Cytokine & Growth Factor Reviews

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Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase originally discovered as the molecular target of the immunosuppressant rapamycin. mTOR forms two compositionally and functionally distinct complexes, mTORC1 and mTORC2, which are crucial for coordinating nutrient, energy, oxygen, and growth factor availability with cellular growth, proliferation, and survival. Recent studies have identified critical, non-redundant roles for mTORC1 and mTORC2 in controlling B cell development, differentiation, and functions, and have highlighted emerging roles of the Folliculin-Fnip protein complex in regulating mTOR and B cell development. In this review, we summarize the basic mechanisms of mTOR signaling; describe what is known about the roles of mTORC1, mTORC2, and the Folliculin/Fnip1 pathway in B cell development and functions; and briefly outline current clinical approaches for targeting mTOR in B cell neoplasms. We conclude by highlighting a few salient questions and future perspectives regarding mTOR in B lineage cells.

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“…Deletion of PI3K inhibited leukemogenesis in a murine model of p190 Ph + ALL. A dual PI3K/MTOR inhibitor was effective on Ph + ALL patient samples (53) and showed synergy with Imatinib (54). The activation of AKT and MTOR signaling also plays a critical role in steroid resistance in ALL (55, 56), and multiple agents targeting the PI3K/AKT/MTOR axis are currently in clinical trials for pediatric ALL [reviewed in Ref.…”

Section: The Biology Of Philadelphia Chromosome-positive Allmentioning

confidence: 99%

Current Concepts in Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

2014

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The t(9;22)(q34;q11) or Philadelphia chromosome creates a BCR–ABL1 fusion gene encoding for a chimeric BCR–ABL1 protein. It is present in 3–4% of pediatric acute lymphoblastic leukemia (Ph+ ALL), and about 25% of adult ALL cases. Prior to the advent of tyrosine kinase inhibitors (TKI), Ph+ ALL was associated with a very poor prognosis despite the use of intensive chemotherapy and frequently hematopoietic stem-cell transplantation (HSCT) in first remission. The development of TKIs revolutionized the therapy of Ph+ ALL. Addition of the first generation ABL1 class TKI imatinib to intensive chemotherapy dramatically increased the survival for children with Ph+ ALL and established that many patients can be cured without HSCT. In parallel, the mechanistic understanding of Ph+ ALL expanded exponentially through careful mapping of pathways downstream of BCR–ABL1, the discovery of mutations in master regulators of B-cell development such as IKZF1 (Ikaros), PAX5, and early B-cell factor (EBF), the recognition of the complex clonal architecture of Ph+ ALL, and the delineation of genomic, epigenetic, and signaling abnormalities contributing to relapse and resistance. Still, many important basic and clinical questions remain unanswered. Current clinical trials are testing second generation TKIs in patients with newly diagnosed Ph+ ALL. Neither the optimal duration of therapy nor the optimal chemotherapy backbone are currently defined. The role of HSCT in first remission and post-transplant TKI therapy also require further study. In addition, it will be crucial to continue to dig deeper into understanding Ph+ ALL at a mechanistic level, and translate findings into complementary targeted approaches. Expanding targeted therapies hold great promise to decrease toxicity and improve survival in this high-risk disease, which provides a paradigm for how targeted therapies can be incorporated into treatment of other high-risk leukemias.

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Mammalian target of rapamycin inhibitor rapamycin enhances anti‐leukemia effect of imatinib on Ph+ acute lymphoblastic leukemia cells

Cited by 17 publications

References 41 publications

High CFTR expression in philadelphia chromosome-positive acute leukemia protects and maintains continuous activation of BCR-ABL and related signaling pathways in combination with PP2A

High CFTR expression in philadelphia chromosome-positive acute leukemia protects and maintains continuous activation of BCR-ABL and related signaling pathways in combination with PP2A

Control of B lymphocyte development and functions by the mTOR signaling pathways

Current Concepts in Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

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