Characterization of a progenitor cell population in childhood T-cell acute lymphoblastic leukemia

Cox, Charlotte V.; Martin, Hannah M.; Kearns, Pamela; Virgo, Paul; Evely, Roger S.; Blair, Allison

doi:10.1182/blood-2006-06-030445

Cited by 133 publications

(120 citation statements)

References 47 publications

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“…181 Moreover, recently it has been shown that active site mTOR inhibitors could induce apoptosis and decrease glucocorticoid resistance in a T-ALL pediatric patient cell subset (CD34 þ /CD7 À /CD4 À ), which is enriched in putative leukemic CICs. 182 Intriguingly, rapamycin was not as effective as the active-site mTOR inhibitors. 183 PTEN plays critical roles in regulating cell cycle progression in HSC and other cells.…”

Section: Mtorc1-hif Drug Resistancementioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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Section: Mtorc1-hif Drug Resistancementioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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“…Active site mTOR inhibitors induce apoptosis in the CD34 þ /CD7 À /CD4 À subset of patient lymphoblasts Finally, we investigated whether PP-242, OSI-027 or AZD-8055 could induce apoptosis in a T-ALL patient lymphoblast subpopulation (CD34 þ /CD7 À /CD4 À ), which is enriched in putative LIC, 20 using quadruple staining and flow-cytometric analysis. After electronic gating on the CD7 À /CD4 À lymphoblast subset, cells were analyzed for CD34 expression and positivity to Annexin V staining.…”

Section: T-all Lymphoblasts Are Sensitive To Active Site Mtor Inhibitorsmentioning

confidence: 99%

“…Unlikely rapamycin, we found a marked inhibition of mRNA translation in T-ALL cell lines treated with active-site mTOR inhibitors. Remarkably, PP-242 and OSI-027 targeted a CD34 þ /CD7 À /CD4 À lymphoblast subset in T-ALL patients, which may correspond to leukemia-initiating cells (LIC) 20 and decreased dexamethasone resistance in this sub-population.…”

Section: Introductionmentioning

confidence: 99%

Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia

et al. 2011

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“…Metformin induces apoptosis in the CD34 þ /CD7 À / CD4 À subset of patient lymphoblasts Finally, we investigated whether metformin could induce apoptosis in a T-ALL patient lymphoblast subpopulation (CD34 þ /CD7 À /CD4 À ), which is enriched in putative LIC, 35 using quadruple staining and flow cytometric analysis. After electronic gating on the CD7 À /CD4 À lymphoblast subset, cells were analyzed for CD34 expression and positivity to Annexin V staining.…”

Section: T-all Lymphoblasts Are Sensitive To Metforminmentioning

confidence: 99%

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

et al. 2011

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The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic subunit of two multi-protein complexes, referred to as mTORC1 and mTORC2. Signaling downstream of mTORC1 has a critical role in leukemic cell biology by controlling mRNA translation of genes involved in both cell survival and proliferation. mTORC1 activity can be down-modulated by upregulating the liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway. Here, we have explored the therapeutic potential of the anti-diabetic drug, metformin (an LKB1/AMPK activator), against both T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples from T-ALL patients displaying mTORC1 activation. Metformin affected T-ALL cell viability by inducing autophagy and apoptosis. However, it was much less toxic against proliferating CD4(+) T-lymphocytes from healthy donors. Western blot analysis demonstrated dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found a marked inhibition of mRNA translation in T-ALL cells treated with metformin. Remarkably, metformin targeted the side population of T-ALL cell lines as well as a putative leukemia-initiating cell subpopulation (CD34(+)/CD7(-)/CD4(+)) in patient samples. In conclusion, metformin displayed a remarkable anti-leukemic activity, which emphasizes future development of LKB1/AMPK activators as clinical candidates for therapy in T-ALL. Leukemia (2012) 26, 91-100; doi:10.1038/leu.2011.269; published online 4 October 201

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Characterization of a progenitor cell population in childhood T-cell acute lymphoblastic leukemia

Cited by 133 publications

References 47 publications

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

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