BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics

Article metrics

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2

References

  1. 1

    Letai AG . Diagnosing and exploiting cancer’s addiction to blocks in apoptosis. Nat Rev Cancer 2008; 8: 121–132.

  2. 2

    Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 2006; 9: 351–365.

  3. 3

    BCL-2 inhibitor yields high response in CLL and SLL. Cancer Discov 2014; 4: OF5.

  4. 4

    Davids MS, Roberts AW, Anderson MA, Pagel JM, Kahl BS, Gerecitano JF et al. The BCL-2-specific BH3-mimetic ABT-199 (GDC-0199) Is active and well-tolerated in patients with relapsed Non-Hodgkin lymphoma: interim results of a Phase I study. ASH Annu Meet Abstr 2012; 120: 304.

  5. 5

    Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013; 19: 202–208.

  6. 6

    Foight GW, Ryan JA, Gullá SV, Letai A, Keating AE . Designed BH3 peptides with high affinity and specificity for targeting Mcl-1 in cells. ACS Chem Biol 2014; 9: 1962–1968.

  7. 7

    Munshi NC, Hideshima T, Carrasco D, Shammas M, Auclair D, Davies F et al. Identification of genes modulated in multiple myeloma using genetically identical twin samples. Blood 2004; 103: 1799–1806.

  8. 8

    Wuillème-Toumi S, Robillard N, Gomez P, Moreau P, Le Gouill S, Avet-Loiseau H et al. Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival. Leukemia 2005; 19: 1248–1252.

  9. 9

    Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol Off J Am Soc Clin Oncol 2012; 30: 488–496.

  10. 10

    Bodet L, Gomez-Bougie P, Touzeau C, Dousset C, Descamps G, Maïga S et al. ABT-737 is highly effective against molecular subgroups of multiple myeloma. Blood 2011; 118: 3901–3910.

  11. 11

    Touzeau C, Dousset C, Le Gouill S, Sampath D, Leverson JD, Souers AJ et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia 2013; 28: 210–212.

  12. 12

    Morales AA, Kurtoglu M, Matulis SM, Liu J, Siefker D, Gutman DM et al. Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL/Bcl-2 in Mcl-1-expressing myeloma cells. Blood 2011; 118: 1329–1339.

  13. 13

    Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov 2014; 4: 362–375.

  14. 14

    Chonghaile TN, Roderick JE, Glenfield C, Ryan J, Sallan SE, Silverman LB et al. Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. Cancer Discov 2014; 4: 1074–1087.

  15. 15

    Kumar S, Vij R, Kaufman J, Mikhael J, Facon T, Moreau P et alPhase I Interim Safety and Efficacy of Venetoclax (ABT-199/GDC-0199) Monotherapy for Relapsed/refractory Multiple Myeloma. J Clin Oncol 2015; 33 (suppl: abstract 8576)..

  16. 16

    Touzeau C, Chanan-Khan A, Roberts AW, Agarwal A, Facon T, Lebovic D et alPhase 1b Interim Results: Venetoclax (ABT-199/GDC-0199) in Combination with Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma. J Clin Oncol 2015; 33 (suppl): abstract 8580..

  17. 17

    Ryan J, Letai A . BH3 profiling in whole cells by fluorimeter or FACS. Methods 2013; 61: 156–164.

Download references

Acknowledgements

We gratefully acknowledge support from NIH grants R01CA129974. CT was supported by the Fondation Française pour la Recherche contre le Myélome et les Gammapathies monoclonales (F.F.R.M.G.).

Author contributions

AL and CT designed the research and wrote the manuscript. CT performed the experiments. CT, AL, JR, TNC analyzed the data. PR, KA, MA, SLG and PM provided myeloma cells. All the authors critically reviewed the manuscript.

Author information

Correspondence to A Letai.

Ethics declarations

Competing interests

AL has been a paid advisor to AbbVie. AL’s laboratory has received sponsorship for research with AbbVie.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Touzeau, C., Ryan, J., Guerriero, J. et al. BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics. Leukemia 30, 761–764 (2016) doi:10.1038/leu.2015.184

Download citation

Further reading