Synergistic activity of rapamycin and dexamethasone in vitro and in vivo in acute lymphoblastic leukemia via cell-cycle arrest and apoptosis

Zhang, Chong; Ryu, Yongku; Chen, Taylor Z.; Hall, Connor P.; Webster, Daniel R.; Kang, Min H.

doi:10.1016/j.leukres.2011.10.022

Cited by 47 publications

(41 citation statements)

References 45 publications

(46 reference statements)

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“…23,26,[38][39][40][41] In those studies, the single-agent activity of MTIs was variable in B-ALL, but more promising in T-cell ALL and high-risk subsets of B-ALL, such as Ph ϩ ALL. 38,40,41 However, rapamycin displays broad anti-ALL …”

Section: Discussionmentioning

confidence: 99%

“…on May 9, 2018. by guest www.bloodjournal.org From activity in combination with chemotherapeutic agents, including dexamethasone, methotrexate, or doxorubicin. 24,[41][42][43][44] To move MTIs successfully into clinical trials, it would be ideal to identify particular subsets of B-ALL that are more likely to respond. Here we show that a leukemia with an activating mutation in IL7R and several leukemias with altered CRLF2 and JAK/STAT signaling are sensitive to rapamycin.…”

Section: Efficacy Of Jak and Mtor Inhibitors In Ph-like All 3515mentioning

confidence: 99%

See 1 more Smart Citation

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia

Maude

Tasian

Vincent

et al. 2012

Blood

260

223

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CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been identified in Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), a recently described subtype of pediatric high-risk B-precursor ALL (B-ALL) which exhibits a gene expression profile similar to Ph-positive ALL and has a poor prognosis. Hyperactive JAK/STAT and PI3K/mammalian target of rapamycin (mTOR) signaling is common in this highrisk subset. We, therefore, investigated the efficacy of the JAK inhibitor ruxolitinib and the mTOR inhibitor rapamycin in xenograft models of 8 pediatric B-ALL cases with and without CRLF2 and JAK genomic lesions. Ruxolitinib treatment yielded significantly lower peripheral blast counts compared with vehicle (P < .05) in 6 of 8 human leukemia xenografts and lower splenic blast counts (P < . IntroductionSurvival rates for childhood B-precursor acute lymphoblastic leukemia (B-ALL) approach 90% with current combination chemotherapy regimens. 1 Intensification of chemotherapy regimens has largely been responsible for dramatic improvements in survival; however, recent modifications have yielded diminishing returns, particularly in a subset of leukemias that are relatively resistant to conventional cytotoxic chemotherapy. The identification of underlying genetic alterations in chemotherapy-resistant subtypes, particularly lesions that drive leukemogenesis and can be targeted with novel therapies, remains an urgent need.Genome-wide analyses and next-generation sequencing approaches have advanced our understanding of potential leukemogenic mutations in pediatric ALL. [2][3][4][5][6][7] Recently, these analyses identified a cohort of clinically high-risk pediatric B-precursor ALL with gene expression profiles similar to those of Philadelphia chromosome-positive ALL (Ph ϩ ALL, also termed BCR-ABL1-positive ALL). 2,4,8 This Ph-like cohort suffers high rates of relapse and mortality. The similarity to Ph ϩ ALL suggests that aberrant kinase activity may also drive this subset of ALL. Indeed, several lesions affecting kinase activity and cytokine signaling have recently been identified in Ph-like ALL. 9 Rearrangements in CRLF2 (cytokine receptor-like factor 2), leading to overexpression of this component of the heterodimeric cytokine receptor for thymic stromal lymphopoietin (TSLP), are present in up to 7% of childhood B-precursor ALL overall, 10-12 represent approximately half of Ph-like ALLs, 8 and are highly associated with point mutations in Janus kinase (JAK) family members. 11,13-15 Moreover, CRLF2 overexpression is an independent negative prognostic factor in high-risk pediatric B-ALL. 16 The frequency of genetic alterations in CRLF2 and JAK2 in high-risk B-ALL and Down syndrome-associated ALL 10,17 suggests that these lesions may be key events in leukemogenesis. Consistent with its role in early B-cell development, we have previously demonstrated that TSLP stimulates proliferation of precursor B-ALL cell lines. 18,19 Similarly, JAK signaling has been implicated in BCR-ABL1-mediated transform...

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Section: Discussionmentioning

confidence: 99%

Section: Efficacy Of Jak and Mtor Inhibitors In Ph-like All 3515mentioning

confidence: 99%

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia

Maude

Tasian

Vincent

et al. 2012

Blood

260

223

View full text Add to dashboard Cite

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“…37 We then investigated whether Dex caused cell cycle arrest in Dex-resistant cells. As expected, treatment with Dex resulted in a dramatic accumulation in the G0/G1 phase of the cell cycle and de-phosphorylation of p-Rb at Ser780 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells

Jiang

Xie

et al. 2015

Cancer Biology & Therapy

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Glucocorticoid (GC) resistance remains a major obstacle to successful treatment of lymphoid malignancies. Till now, the precise mechanism of GC resistance remains unclear. In the present study, dexamethasone (Dex) inhibited cell proliferation, arrested cell cycle in G0/G1-phase, and induced apoptosis in Dex-sensitive acute lymphoblastic leukemia cells. However, Dex failed to cause cell death in Dex-resistant lymphoid malignant cells. Intriguingly, we found that autophagy was induced by Dex in resistant cells, as indicated by autophagosomes formation, LC3-I to LC3-II conversion, p62 degradation, and formation of acidic autophagic vacuoles. Moreover, the results showed that Dex reduced the activity of mTOR pathway, as determined by decreased phosphorylation levels of mTOR, Akt, P70S6K and 4E-BP1 in resistant cells. Inhibition of autophagy by either chloroquine (CQ) or 3-methyladenine (3-MA) overcame Dex-resistance in lymphoid malignant cells by increasing apoptotic cell death in vitro. Consistently, inhibition of autophagy by stably knockdown of Beclin1 sensitized Dex-resistant lymphoid malignant cells to induction of apoptosis in vivo. Thus, inhibition of autophagy has the potential to improve lymphoid malignancy treatment by overcoming GC resistance.

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“…Inhibitors of the PI3-kinase pathway enhanced GC induced apoptosis in human lymphoma cells (28), which indicate a positive feedback between glucocorticoids/GR␣ and PTEN in the suppression of growth. The interplay between GR␣ and PTEN was demonstrated in T-cells extracted from human leukemia patients, which had increased PTEN expression following GC treatment (29). However, patients that relapsed had a complete loss of PTEN expression.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

Stechschulte

Wuescher

Marino

et al. 2014

Journal of Biological Chemistry

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Background:The glucocorticoid receptor ␤ (GR␤) is a positive regulator of growth. Results: GR␤ suppression of PTEN resulted in enhanced phosphorylation of Akt and growth. Conclusion: GR␤ enhances insulin-induced proliferation by suppressing PTEN and activating Akt1. Significance: GR␤ suppression of PTEN indicates that it has an important role in growth factor signaling and potentially cancer.

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Synergistic activity of rapamycin and dexamethasone in vitro and in vivo in acute lymphoblastic leukemia via cell-cycle arrest and apoptosis

Cited by 47 publications

References 45 publications

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia

Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

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