The effect of TLX3 expression on the prognosis of pediatric T cell acute lymphocytic leukemia—a systematic review

Ma, Jiexian; Hua, Jinsheng; Sha, Yinghao; Xie, Yanhui

doi:10.1007/s13277-014-1873-5

Cited by 3 publications

(5 citation statements)

References 23 publications

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“…1 Pediatric T-ALL patients show a dismal outcome in comparison with B-ALL, with a 25% to 30% of cases not able to ever achieve a complete remission and thus experience relapse. 2 To overcome drug resistance, possibly avoiding high-dose ineffective overtreatment, we urgently need new, more specific targeted therapies. One of the first signs of drug resistance during pediatric ALL treatment following AIEOP-BFM protocols is the PB blast count after the first 7 days of steroid prephase.…”

Section: Discussionmentioning

confidence: 99%

“…T-ALL accounts for approximately the 10% to 15% of cases, 1 and it is historically associated with an inferior outcome in comparison with B-ALL, mainly because of an increased relapse risk, with relapsed T-ALL patients having a particularly dismal outcome. 2 With contemporary risk-adapted therapy protocols, the outcome for pediatric T-ALL improved, approaching cure rates of 70%, 3 but the aggressive high-dose multiagent treatment regimens are often associated with severe acute toxicities and long-term side effects. 4 Pediatric T-ALL patients frequently experience chemotherapy resistance, showing a lower clearance of leukemic blasts during induction therapy than do B-ALL patients and a higher proportion of no response to the first 7 days of glucocorticoid (GC) treatment.…”

Section: Introductionmentioning

confidence: 99%

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Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia

Serafin¹,

Capuzzo²,

Milani³

et al. 2017

Blood

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Pediatric T-acute lymphoblastic leukemia (T-ALL) patients often display resistance to glucocorticoid (GC) treatment. These patients, classified as prednisone poor responders (PPR), have poorer outcome than do the other pediatric T-ALL patients receiving a high-risk adapted therapy. Because glucocorticoids are administered to ALL patients during all the different phases of therapy, GC resistance represents an important challenge to improving the outcome for these patients. Mechanisms underlying resistance are not yet fully unraveled; thus our research focused on the identification of deregulated signaling pathways to point out new targeted approaches. We first identified, by reverse-phase protein arrays, the lymphocyte cell-specific protein-tyrosine kinase (LCK) as aberrantly activated in PPR patients. We showed that LCK inhibitors, such as dasatinib, bosutinib, nintedanib, and WH-4-023, are able to induce cell death in GC-resistant T-ALL cells, and remarkably, cotreatment with dexamethasone is able to reverse GC resistance, even at therapeutic drug concentrations. This was confirmed by specific gene silencing and ex vivo combined treatment of cells from PPR patient-derived xenografts. Moreover, we observed that LCK hyperactivation in PPR patients upregulates the calcineurin/nuclear factor of activated T cells signaling triggering to interleukin-4 () overexpression. GC-sensitive cells cultured with IL-4 display an increased resistance to dexamethasone, whereas the inhibition of IL-4 signaling could increase GC-induced apoptosis in resistant cells. Treatment with dexamethasone and dasatinib also impaired engraftment of leukemia cells in vivo. Our results suggest a quickly actionable approach to supporting conventional therapies and overcoming GC resistance in pediatric T-ALL patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia

Serafin¹,

Capuzzo²,

Milani³

et al. 2017

Blood

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“…Acute myeloid leukemia (AML) is a severe malignant cancer worldwide [1]. Although detected mainly in teenagers and adults, pediatric cases comprise a certain percentage of newly diagnosed AML patients [1].…”

Section: Introductionmentioning

confidence: 99%

“…Although detected mainly in teenagers and adults, pediatric cases comprise a certain percentage of newly diagnosed AML patients [1]. The etiology and pathology of AML in children are not completely determined [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside Rh2 Mitigates Pediatric Leukemia Through Suppression of Bcl-2 in Leukemia Cells

Wang

2015

Cell Physiol Biochem

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Background/Aims: Acute myeloid leukemia (AML) is a severe malignant cancer worldwide, in both adult and pediatric patients. Since bone marrow cell transplantation is seriously limited by the availability of the immune-paired donor sources, the therapy for pediatric leukemia remains challenging. Ginsenoside Rh2 (GRh2) is a well-characterized component in red ginseng, and has established therapeutic effects for different diseases, although whether GRh2 may have a therapeutic effect on pediatric leukemia has not been investigated. Methods: We examined the effects of GRh2 on the survival of mice in an acute leukemia model. We analyzed the effects of GRh2 on the cell viability of leukemia cell lines in vitro, using a CCK-8 assay and an MTT assay. We analyzed the effects of GRh2 on the apoptosis of leukemia cell lines in vitro, by flow cytometry. We analyzed the levels of Bcl-2 and microRNA-21 (miR-21) in GRh2-treated leukemia cells. Prediction of binding between miR-21 and 3'-UTR of Bcl-2 mRNA was performed by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. Results: GRh2 significantly prolonged the survival of mice with pediatric leukemia. GRh2 significantly decreased the viability of leukemia cells in vitro, through induction of apoptosis. GRh2 significantly decreased the levels of an anti-apoptotic protein Bcl-2 in leukemia cells, possibly through induction of miR-21, which suppressed the translation of Bcl-2 mRNA via 3'-UTR binding. Conclusion: GRh2 may be an effective treatment for pediatric leukemia, and GRh2 may induce apoptosis of leukemia cells through miR-21-modulated suppression of Bcl-2.

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“…Leukemia is a severe malignant cancer worldwide [1]. Although leukemia is mainly detected in adults, some are indeed detected during pediatric period as pediatric leukemia (PL) [1]. The etiology and pathology of leukemia in children remain elusive [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Role of Beclin-1-Mediated Autophagy in the Survival of Pediatric Leukemia Cells

Feng²,

Zhao³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Acute and chronic leukemia are severe malignant cancers worldwide, and can occur in pediatric patients. Since bone marrow cell transplantation is seriously limited by the availability of the immune-paired donor sources, the therapy for pediatric leukemia (PL) remains challenging. Autophagy is essential for the regulation of cell survival in the harsh environment. However, the role of autophagy in the survival of PL cells under the oxidative stress, e.g. chemotherapy, remain ill-defined. In the current study, we addressed these questions. Methods: We analyzed the effects of oxidative stress on the cell viability of PL cells in vitro, using a CCK-8 assay. We analyzed the effects of oxidative stress on the apoptosis and autophagy of PL cells. We analyzed the levels of Beclin-1 and microRNA-93 (miR-93) in PL cells. Prediction of binding between miR-93 and 3'-UTR of Beclin-1 mRNA was performed by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The relationship between levels of miR-93 and patients' survival was analyzed in PL patients. Results: We found that oxidative stress dose-dependently increased autophagy in PL cells. While low-level oxidative stress did not increase apoptosis, high-level oxidative stress increased apoptosis, seemingly from failure of autophagy-mediated cell survival. High-level oxidative stress appeared to suppress the protein levels of an autophagy protein Beclin-1 in PL cells, possibly through induction of miR-93, which inhibited the translation of Beclin-1 mRNA via 3'-UTR binding. Conclusion: Beclin-1-mediated autophagy plays a key role in the survival of PL cells against oxidative stress. Induction of miR-93 may increase the sensitivity of PL cells to oxidative stress during chemotherapy to improve therapeutic outcome.

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The effect of TLX3 expression on the prognosis of pediatric T cell acute lymphocytic leukemia—a systematic review

Cited by 3 publications

References 23 publications

Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia

Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia

Ginsenoside Rh2 Mitigates Pediatric Leukemia Through Suppression of Bcl-2 in Leukemia Cells

Role of Beclin-1-Mediated Autophagy in the Survival of Pediatric Leukemia Cells

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