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The BH3-mimetic ABT-737 effectively kills acute myeloid leukemia initiating cells.

Baev DV, Krawczyk J, O׳Dwyer M, Szegezdi E - Leuk Res Rep (2014)

Bottom Line: The anti-apoptotic proteins Bcl-XL and Bcl-2 are abundantly expressed in hematopoietic stem cells and/or progenitor cells.The efficacy of ABT-737 against AML blasts and the primitive CD34(+)/CD38(-) population was equal and independent of sensitivity to cytarabine/daunorubicin.These results, together with previously reported synergistic effects of ABT-737 with chemotherapeutics make BH3-mimetics promising candidates for future AML treatment regimens.

View Article: PubMed Central - PubMed

Affiliation: Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Biosciences, Dangan, Galway, Ireland.

ABSTRACT
The anti-apoptotic proteins Bcl-XL and Bcl-2 are abundantly expressed in hematopoietic stem cells and/or progenitor cells. Furthermore, leukemic cells expressing these proteins are enriched in minimal residual disease cell populations. This prompted us to test the BH3-mimetic compound ABT-737 for its ability to eradicate putative leukemic stem cells. ABT-737 demonstrated potent cytotoxic effects in all patient samples tested. The efficacy of ABT-737 against AML blasts and the primitive CD34(+)/CD38(-) population was equal and independent of sensitivity to cytarabine/daunorubicin. These results, together with previously reported synergistic effects of ABT-737 with chemotherapeutics make BH3-mimetics promising candidates for future AML treatment regimens.

No MeSH data available.


Related in: MedlinePlus

ABT-737 has a potent cytotoxic effect on bone marrow-derived AML pLSCs. Bone marrow-derived primary AML cells were cultured on a stromal-feeder layer for 24 h and then treated with 30 nM and 300 nM of ABT-737 for 24 h. AML cell viability was evaluated using7-AAD staining and flow cytometry. (A) The cytotoxic effect of ABT-737 on the overall blast population. The graph shows the percentage of live cells for each sample. (B) ABT-737 is equally efficient in eradicating AML pLSCs. The graph shows the percentage of the CD34+/CD38− cells within the surviving AML cell population in each sample. E Horizontal lines indicate mean values. Different shapes indicate data-points corresponding to particular patient samples (Patients cross-referencing with Table 1: Patient 1 (○), Patient 2 (■), Patient 3 (•), Patient 4 (□)).
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f0005: ABT-737 has a potent cytotoxic effect on bone marrow-derived AML pLSCs. Bone marrow-derived primary AML cells were cultured on a stromal-feeder layer for 24 h and then treated with 30 nM and 300 nM of ABT-737 for 24 h. AML cell viability was evaluated using7-AAD staining and flow cytometry. (A) The cytotoxic effect of ABT-737 on the overall blast population. The graph shows the percentage of live cells for each sample. (B) ABT-737 is equally efficient in eradicating AML pLSCs. The graph shows the percentage of the CD34+/CD38− cells within the surviving AML cell population in each sample. E Horizontal lines indicate mean values. Different shapes indicate data-points corresponding to particular patient samples (Patients cross-referencing with Table 1: Patient 1 (○), Patient 2 (■), Patient 3 (•), Patient 4 (□)).

Mentions: ABT-737 is a BH3-mimetic targeting Bcl-2, Bcl-XL and Bcl-W. The aim of the experiments was to test whether inhibition of Bcl-2 and Bcl-XL using ABT-737 can eradicate the CD34+/CD38− AML cell population. Bone marrow MNCs from patients (Table 1) were cultured on stromal-feeder layer for 24 h and then treated with dosages of ABT-737 of 30 nM and 300 nM. The co-culture system has been optimized for supporting the survival of AML cells ex vivo and to model features of the bone marrow microenvironment that drive drug-resistance [8]. The dose range was selected based on the in vitro effect of ABT-737 on secondary AML cell lines [8]. The resting cell viability of the patient samples was between 60% and 90% after 24 h of stromal-feeder co-culture. ABT-737 potently killed the AML cells in all samples with the 300 nM dose causing a 75% average loss in viability (Fig.1A). Similar results were obtained from a parallel study with ALL patient samples [data not shown].


The BH3-mimetic ABT-737 effectively kills acute myeloid leukemia initiating cells.

Baev DV, Krawczyk J, O׳Dwyer M, Szegezdi E - Leuk Res Rep (2014)

ABT-737 has a potent cytotoxic effect on bone marrow-derived AML pLSCs. Bone marrow-derived primary AML cells were cultured on a stromal-feeder layer for 24 h and then treated with 30 nM and 300 nM of ABT-737 for 24 h. AML cell viability was evaluated using7-AAD staining and flow cytometry. (A) The cytotoxic effect of ABT-737 on the overall blast population. The graph shows the percentage of live cells for each sample. (B) ABT-737 is equally efficient in eradicating AML pLSCs. The graph shows the percentage of the CD34+/CD38− cells within the surviving AML cell population in each sample. E Horizontal lines indicate mean values. Different shapes indicate data-points corresponding to particular patient samples (Patients cross-referencing with Table 1: Patient 1 (○), Patient 2 (■), Patient 3 (•), Patient 4 (□)).
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f0005: ABT-737 has a potent cytotoxic effect on bone marrow-derived AML pLSCs. Bone marrow-derived primary AML cells were cultured on a stromal-feeder layer for 24 h and then treated with 30 nM and 300 nM of ABT-737 for 24 h. AML cell viability was evaluated using7-AAD staining and flow cytometry. (A) The cytotoxic effect of ABT-737 on the overall blast population. The graph shows the percentage of live cells for each sample. (B) ABT-737 is equally efficient in eradicating AML pLSCs. The graph shows the percentage of the CD34+/CD38− cells within the surviving AML cell population in each sample. E Horizontal lines indicate mean values. Different shapes indicate data-points corresponding to particular patient samples (Patients cross-referencing with Table 1: Patient 1 (○), Patient 2 (■), Patient 3 (•), Patient 4 (□)).
Mentions: ABT-737 is a BH3-mimetic targeting Bcl-2, Bcl-XL and Bcl-W. The aim of the experiments was to test whether inhibition of Bcl-2 and Bcl-XL using ABT-737 can eradicate the CD34+/CD38− AML cell population. Bone marrow MNCs from patients (Table 1) were cultured on stromal-feeder layer for 24 h and then treated with dosages of ABT-737 of 30 nM and 300 nM. The co-culture system has been optimized for supporting the survival of AML cells ex vivo and to model features of the bone marrow microenvironment that drive drug-resistance [8]. The dose range was selected based on the in vitro effect of ABT-737 on secondary AML cell lines [8]. The resting cell viability of the patient samples was between 60% and 90% after 24 h of stromal-feeder co-culture. ABT-737 potently killed the AML cells in all samples with the 300 nM dose causing a 75% average loss in viability (Fig.1A). Similar results were obtained from a parallel study with ALL patient samples [data not shown].

Bottom Line: The anti-apoptotic proteins Bcl-XL and Bcl-2 are abundantly expressed in hematopoietic stem cells and/or progenitor cells.The efficacy of ABT-737 against AML blasts and the primitive CD34(+)/CD38(-) population was equal and independent of sensitivity to cytarabine/daunorubicin.These results, together with previously reported synergistic effects of ABT-737 with chemotherapeutics make BH3-mimetics promising candidates for future AML treatment regimens.

View Article: PubMed Central - PubMed

Affiliation: Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Biosciences, Dangan, Galway, Ireland.

ABSTRACT
The anti-apoptotic proteins Bcl-XL and Bcl-2 are abundantly expressed in hematopoietic stem cells and/or progenitor cells. Furthermore, leukemic cells expressing these proteins are enriched in minimal residual disease cell populations. This prompted us to test the BH3-mimetic compound ABT-737 for its ability to eradicate putative leukemic stem cells. ABT-737 demonstrated potent cytotoxic effects in all patient samples tested. The efficacy of ABT-737 against AML blasts and the primitive CD34(+)/CD38(-) population was equal and independent of sensitivity to cytarabine/daunorubicin. These results, together with previously reported synergistic effects of ABT-737 with chemotherapeutics make BH3-mimetics promising candidates for future AML treatment regimens.

No MeSH data available.


Related in: MedlinePlus