Acute myeloid leukemia cells harboring MLL fusion genes or with the acute promyelocytic leukemia phenotype are sensitive to the Bcl-2-selective inhibitor ABT-199

doi:10.1038/leu.2014.72

. 2014 Jul;28(7):1557-60.

doi: 10.1038/leu.2014.72. Epub 2014 Feb 17.

Acute myeloid leukemia cells harboring MLL fusion genes or with the acute promyelocytic leukemia phenotype are sensitive to the Bcl-2-selective inhibitor ABT-199

X Niu¹, G Wang², Y Wang³, J T Caldwell⁴, H Edwards⁵, C Xie⁶, J W Taub⁷, C Li³, H Lin⁸, Y Ge⁶

Affiliations

¹ National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology & Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China.
² 1] National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology & Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China [2] Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
³ Department of Pediatric Hematology and Oncology, The First Hospital of Jilin University, Changchun, China.
⁴ 1] Wayne State University School of Medicine, Detroit, MI, USA [2] Cancer Biology Graduate Program, Wayne State School of Medicine, Detroit, MI, USA.
⁵ 1] Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA [2] Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
⁶ 1] National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology & Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China [2] Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA [3] Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
⁷ 1] Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA [2] Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA [3] Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
⁸ Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, China.

PMID: 24531733
PMCID: PMC4090260
DOI: 10.1038/leu.2014.72

Acute myeloid leukemia cells harboring MLL fusion genes or with the acute promyelocytic leukemia phenotype are sensitive to the Bcl-2-selective inhibitor ABT-199

X Niu et al. Leukemia. 2014 Jul.

. 2014 Jul;28(7):1557-60.

doi: 10.1038/leu.2014.72. Epub 2014 Feb 17.

Authors

X Niu¹, G Wang², Y Wang³, J T Caldwell⁴, H Edwards⁵, C Xie⁶, J W Taub⁷, C Li³, H Lin⁸, Y Ge⁶

Affiliations

¹ National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology & Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China.
² 1] National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology & Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China [2] Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
³ Department of Pediatric Hematology and Oncology, The First Hospital of Jilin University, Changchun, China.
⁴ 1] Wayne State University School of Medicine, Detroit, MI, USA [2] Cancer Biology Graduate Program, Wayne State School of Medicine, Detroit, MI, USA.
⁵ 1] Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA [2] Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
⁶ 1] National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology & Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China [2] Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA [3] Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
⁷ 1] Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA [2] Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA [3] Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
⁸ Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, China.

PMID: 24531733
PMCID: PMC4090260
DOI: 10.1038/leu.2014.72

No abstract available

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Conflict of interest statement

Conflict of Interest: The authors declare no conflict of interest.

Figures

**Figure 1**
**Panel A:** Cell lines were treated with ABT-199 for 24 h. Apoptotic events (Annexin V+) were determined by Annexin V/PI staining and flow cytometry analyses. **Panel B:** AML cell lines were cultured for 72 h in the presence of variable concentrations of ABT-199 and viable cell numbers were determined using MTT reagent and a microplate reader. IC₅₀ values were calculated as drug concentration necessary to inhibit 50% proliferation compared to untreated control cells. The horizontal lines indicate the median. **Panel C:** Freshly isolated AML patient samples were purified by standard Ficoll-Hypaque density centrifugation. AML patient samples #10 and #12 were treated with ABT-199 for 24 h and apoptotic events were determined by Annexin V/PI staining and flow cytometry analyses. **Panel D:** *Ex vivo* ABT-199 sensitivity was determined using MTT assays. The horizontal lines indicate median ABT-199 IC₅₀s in each group of AML patient samples (Panel D). **Panel E:** Total RNAs were isolated and gene transcript levels were determined by Real-time RT-PCR. Transcript levels were normalized to GAPDH and relative expression levels were calculated using the comparative Ct method (comparing all samples to the CMS cell line expression levels). The Bcl-2/Mcl-1 ratios for the AML cell line and patient samples were graphed against the ABT-199 IC₅₀. **Panel F:** MV4-11 cells were infected with Precision LentiORF Mcl-1, Bcl-xL, or red fluorescent protein control (designated MV4-11/Mcl-1, MV4-11/Bcl-xL, and MV4-11/RFP respectively) lentivirus overnight, washed, and incubated for 48 h prior to adding selection drug (blasticidin) to the culture medium. Whole cell lysates were subjected to Western blotting and probed with anti-Bcl-xL, -Mcl-1, -Bcl-2 or –β-actin antibody. **Panel G:** MV4-11/Mcl-1, MV4-11/Bcl-xL, and MV4-11/RFP were treated with ABT-199 for 24 h and apoptotic events were determined by Annexin V/PI staining and flow cytometry analyses. The p values were calculated using the Mann-Whitney U test. The relationship between the Bcl-2 family transcript levels/ratios and ABT-199 sensitivity were determined by the nonparametric Spearman rank correlation coefficient.

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References

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA: a cancer journal for clinicians. 2013;63 (1):11–30. - PubMed
1. Rubnitz JE, Inaba H, Dahl G, Ribeiro RC, Bowman WP, Taub J, et al. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. The lancet oncology. 2010;11(6):543–52. - PMC - PubMed
1. Saxena A, Viswanathan S, Moshynska O, Tandon P, Sankaran K, Sheridan DP. Mcl-1 and Bcl-2/Bax ratio are associated with treatment response but not with Rai stage in B-cell chronic lymphocytic leukemia. American journal of hematology. 2004;75(1):22–33. - PubMed
1. Lauria F, Raspadori D, Rondelli D, Ventura MA, Fiacchini M, Visani G, et al. High bcl-2 expression in acute myeloid leukemia cells correlates with CD34 positivity and complete remission rate. Leukemia. 1997;11(12):2075–8. - PubMed
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[1] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA: a cancer journal for clinicians. 2013;63 (1):11–30. - PubMed

[2] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA: a cancer journal for clinicians. 2013;63 (1):11–30. - PubMed

[3] Rubnitz JE, Inaba H, Dahl G, Ribeiro RC, Bowman WP, Taub J, et al. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. The lancet oncology. 2010;11(6):543–52. - PMC - PubMed

[4] Rubnitz JE, Inaba H, Dahl G, Ribeiro RC, Bowman WP, Taub J, et al. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. The lancet oncology. 2010;11(6):543–52. - PMC - PubMed

[5] Saxena A, Viswanathan S, Moshynska O, Tandon P, Sankaran K, Sheridan DP. Mcl-1 and Bcl-2/Bax ratio are associated with treatment response but not with Rai stage in B-cell chronic lymphocytic leukemia. American journal of hematology. 2004;75(1):22–33. - PubMed

[6] Saxena A, Viswanathan S, Moshynska O, Tandon P, Sankaran K, Sheridan DP. Mcl-1 and Bcl-2/Bax ratio are associated with treatment response but not with Rai stage in B-cell chronic lymphocytic leukemia. American journal of hematology. 2004;75(1):22–33. - PubMed

[7] Lauria F, Raspadori D, Rondelli D, Ventura MA, Fiacchini M, Visani G, et al. High bcl-2 expression in acute myeloid leukemia cells correlates with CD34 positivity and complete remission rate. Leukemia. 1997;11(12):2075–8. - PubMed

[8] Lauria F, Raspadori D, Rondelli D, Ventura MA, Fiacchini M, Visani G, et al. High bcl-2 expression in acute myeloid leukemia cells correlates with CD34 positivity and complete remission rate. Leukemia. 1997;11(12):2075–8. - PubMed

[9] Davids MS, Letai A. _targeting the B-cell lymphoma/leukemia 2 family in cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(25):3127–35. - PMC - PubMed

[10] Davids MS, Letai A. _targeting the B-cell lymphoma/leukemia 2 family in cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(25):3127–35. - PMC - PubMed

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Acute myeloid leukemia cells harboring MLL fusion genes or with the acute promyelocytic leukemia phenotype are sensitive to the Bcl-2-selective inhibitor ABT-199

Affiliations

Acute myeloid leukemia cells harboring MLL fusion genes or with the acute promyelocytic leukemia phenotype are sensitive to the Bcl-2-selective inhibitor ABT-199

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