Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chronic lymphocytic leukemia

Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199)

Leukemia volume 31, pages 1872–1881 (2017)Cite this article

Subjects

Abstract

Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin’s lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes. In concert with induction of transcript levels, reverse phase protein arrays and immunoblots confirmed increase at the protein level. The BCL2 inhibitor venetoclax induced greater apoptosis in ex vivo-cultured CLL cells obtained from patients on duvelisib compared with pre-treatment CLL cells from the same patients. In vitro combination of duvelisib and venetoclax resulted in enhanced apoptosis even in CLL cells cultured under conditions that simulate the tumor microenvironment. These data provide a mechanistic rationale for testing the combination of duvelisib and venetoclax in the clinic. Such combination regimen (NCT02640833) is being evaluated for patients with B-cell malignancies including CLL.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Montserrat E, Moreno C . Chronic lymphocytic leukaemia: a short overview. Ann Oncol 2008; 19 (Suppl 7): vii320–vii325.

    PubMed  Google Scholar 

  2. Chiorazzi N, Rai KR, Ferrarini M . Chronic lymphocytic leukemia. N Engl J Med 2005; 352: 804–815.

    Article  CAS  PubMed  Google Scholar 

  3. Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 2011; 117: 563–574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Burger JA, Gribben JG . The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies. Semin Cancer Biol 2014; 24: 71–81.

    Article  CAS  PubMed  Google Scholar 

  5. Tomlinson MG, Woods DB, McMahon M, Wahl MI, Witte ON, Kurosaki T et al. A conditional form of Bruton's tyrosine kinase is sufficient to activate multiple downstream signaling pathways via PLC Gamma 2 in B cells. BMC Immunol 2001; 2: 4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yang Q, Modi P, Newcomb T, Queva C, Gandhi V . Idelalisib: first-in-class PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and follicular lymphoma. Clin Cancer Res 2015; 21: 1537–1542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Winkler DG, Faia KL, DiNitto JP, Ali JA, White KF, Brophy EE et al. PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol 2013; 20: 1364–1374.

    Article  CAS  PubMed  Google Scholar 

  8. Balakrishnan K, Peluso M, Fu M, Rosin NY, Burger JA, Wierda WG et al. The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL. Leukemia 2015; 29: 1811–1822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Peluso M, Faia K, Winkler D, Patel N, Brophy E, White K et al. Duvelisib (IPI-145) inhibits malignant B-cell proliferation and disrupts signaling from the tumor microenvironment through mechanisms that are dependent on PI3K-δ and PI3K-γ. Blood 2014; 124: 328–328.

    Article  Google Scholar 

  10. O'Brien S, Patel M, Kahl BS, Horwitz SM, Foss FM, Porcu P et al. Duvelisib (IPI-145), a PI3K-δ, γ Inhibitor, Is Clinically Active in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. Blood 2014; 124: 3334.

    Google Scholar 

  11. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369: 32–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med 2016; 374: 323–332.

    Article  CAS  PubMed  Google Scholar 

  13. Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014; 123: 3390–3397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370: 997–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2014; 15: 48–58.

    Article  CAS  PubMed  Google Scholar 

  16. Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015; 125: 2497–2506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Patel MR, O'Brien SM, Faia K, White K, Douglas M, Allen K et al. Early clinical activity and pharmacodynamic effects of duvelisib, a PI3K-{delta},{gamma} inhibitor, in patients with treatment-naive CLL. ASCO Meeting Abstracts 2015; 33 (15_suppl): 7074.

    Google Scholar 

  18. Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med 2014; 370: 2286–2294.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. Blood 1998; 91: 3379–3389.

    CAS  PubMed  Google Scholar 

  20. Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A . Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 2007; 117: 112–121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Davids MS, Deng J, Wiestner A, Lannutti BJ, Wang L, Wu CJ et al. Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia. Blood 2012; 120: 3501–3509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL et al. Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotechnol 2008; 26: 317–325.

    Article  CAS  PubMed  Google Scholar 

  23. Patel V, Chen LS, Wierda WG, Balakrishnan K, Gandhi V . Impact of bone marrow stromal cells on Bcl-2 family members in chronic lymphocytic leukemia. Leuk Lymphoma 2014; 55: 899–910.

    Article  CAS  PubMed  Google Scholar 

  24. Patel V, Balakrishnan K, Keating MJ, Wierda WG, Gandhi V . Expression of executioner procaspases and their activation by a procaspase-activating compound in chronic lymphocytic leukemia cells. Blood 2015; 125: 1126–1136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Packham G, Stevenson FK . Bodyguards and assassins: Bcl-2 family proteins and apoptosis control in chronic lymphocytic leukaemia. Immunology 2005; 114: 441–449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Buggins AG, Pepper CJ . The role of Bcl-2 family proteins in chronic lymphocytic leukaemia. Leuk Res 2010; 34: 837–842.

    Article  CAS  PubMed  Google Scholar 

  27. Al-Harbi S, Hill BT, Mazumder S, Singh K, Devecchio J, Choudhary G et al. An antiapoptotic BCL-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737. Blood 2011; 118: 3579–3590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pepper C, Bentley P, Hoy T . Regulation of clinical chemoresistance by bcl-2 and bax oncoproteins in B-cell chronic lymphocytic leukaemia. Br J Haematol 1996; 95: 513–517.

    Article  CAS  PubMed  Google Scholar 

  29. 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. Am J Hematol 2004; 75: 22–33.

    Article  CAS  PubMed  Google Scholar 

  30. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 1997; 275: 1129–1132.

    Article  CAS  PubMed  Google Scholar 

  31. Bojarczuk K, Sasi BK, Gobessi S, Innocenti I, Pozzato G, Laurenti L et al. BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199. Blood 2016; 127: 3192–3201.

    Article  CAS  PubMed  Google Scholar 

  32. Vaux DL, Cory S, Adams JM . Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988; 335: 440–442.

    Article  CAS  PubMed  Google Scholar 

  33. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ . Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990; 348: 334–336.

    Article  CAS  PubMed  Google Scholar 

  34. Ewings KE, Hadfield-Moorhouse K, Wiggins CM, Wickenden JA, Balmanno K, Gilley R et al. ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL. EMBO J 2007; 26: 2856–2867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cervantes-Gomez F, Lamothe B, Woyach JA, Wierda WG, Keating MJ, Balakrishnan K et al. Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res 2015; 21: 3705–3715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Douglas M, Allen K, Sweeney J, O'Brien SM, Flinn I, Horwitz SM et al. Serum chemokines and cytokines in CLL patients treated with duvelisib, a PI3K-{delta},{gamma} inhibitor. ASCO Meeting Abstracts 2015; 33 (15_suppl): 7072.

    Google Scholar 

  37. Gilling CE, Mittal AK, Chaturvedi NK, Iqbal J, Aoun P, Bierman PJ et al. Lymph node-induced immune tolerance in chronic lymphocytic leukaemia: a role for caveolin-1. Br J Haematol 2012; 158: 216–231.

    Article  CAS  PubMed  Google Scholar 

  38. Herman SE, Niemann CU, Farooqui M, Jones J, Mustafa RZ, Lipsky A et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia 2014; 28: 2188–2196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wodarz D, Garg N, Komarova NL, Benjamini O, Keating MJ, Wierda WG et al. Kinetics of CLL cells in tissues and blood during therapy with the BTK inhibitor ibrutinib. Blood 2014; 123: 4132–4135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fruman DA, Rommel C . PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 2014; 13: 140–156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 2000; 275: 10761–10766.

    Article  CAS  PubMed  Google Scholar 

  42. Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999; 286: 1735–1738.

    Article  CAS  PubMed  Google Scholar 

  43. Egle A, Harris AW, Bouillet P, Cory S . Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci USA 2004; 101: 6164–6169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Enders A, Bouillet P, Puthalakath H, Xu Y, Tarlinton DM, Strasser A . Loss of the pro-apoptotic BH3-only Bcl-2 family member Bim inhibits BCR stimulation-induced apoptosis and deletion of autoreactive B cells. J Exp Med 2003; 198: 1119–1126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Paterson A, Mockridge CI, Adams JE, Krysov S, Potter KN, Duncombe AS et al. Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia. Blood 2012; 119: 1726–1736.

    Article  CAS  PubMed  Google Scholar 

  46. O'Reilly LA, Kruse EA, Puthalakath H, Kelly PN, Kaufmann T, Huang DC et al. MEK/ERK-mediated phosphorylation of Bim is required to ensure survival of T and B lymphocytes during mitogenic stimulation. J Immunol 2009; 183: 261–269.

    Article  CAS  PubMed  Google Scholar 

  47. Luciano F, Jacquel A, Colosetti P, Herrant M, Cagnol S, Pages G et al. Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function. Oncogene 2003; 22: 6785–6793.

    Article  CAS  PubMed  Google Scholar 

  48. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochimica Biophys Acta 2007; 1773: 1263–1284.

    Article  CAS  Google Scholar 

  49. Portell CA, Axelrod M, Brett LK, Gordon VL, Capaldo B, Xing JC et al. Synergistic cytotoxicity of ibrutinib and the BCL2 antagonist, ABT-199(GDC-0199) in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL): molecular analysis reveals mechanisms of target interactions. Blood 2014; 124: 509.

    Google Scholar 

  50. Guarini A, Chiaretti S, Tavolaro S, Maggio R, Peragine N, Citarella F et al. BCR ligation induced by IgM stimulation results in gene expression and functional changes only in IgV H unmutated chronic lymphocytic leukemia (CLL) cells. Blood 2008; 112: 782–792.

    Article  CAS  PubMed  Google Scholar 

  51. Burger JA, Quiroga MP, Hartmann E, Burkle A, Wierda WG, Keating MJ et al. High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation. Blood 2009; 113: 3050–3058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Quiroga MP, Balakrishnan K, Kurtova AV, Sivina M, Keating MJ, Wierda WG et al. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood 2009; 114: 1029–1037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Krysov S, Steele AJ, Coelho V, Linley A, Sanchez Hidalgo M, Carter M et al. Stimulation of surface IgM of chronic lymphocytic leukemia cells induces an unfolded protein response dependent on BTK and SYK. Blood 2014; 124: 3101–3109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rozovski U, Wu JY, Harris DM, Liu Z, Li P, Hazan-Halevy I et al. Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells. Blood 2014; 123: 3797–3802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tavolaro S, Colombo T, Chiaretti S, Peragine N, Fulci V, Ricciardi MR et al. Increased chronic lymphocytic leukemia proliferation upon IgM stimulation is sustained by the upregulation of miR-132 and miR-212. Genes Chromosomes Cancer 2015; 54: 222–234.

    Article  CAS  PubMed  Google Scholar 

  56. Yang Q, Chen LS, Ha MJ, Do KA, Neelapu SS, Gandhi V . Idelalisib impacts cell growth through inhibiting translation regulatory mechanisms in mantle cell lymphoma. Clin Cancer Res 2017; 23: 181–192.

    Article  CAS  PubMed  Google Scholar 

  57. Herman SE, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 2010; 116: 2078–2088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Plander M, Seegers S, Ugocsai P, Diermeier-Daucher S, Ivanyi J, Schmitz G et al. Different proliferative and survival capacity of CLL-cells in a newly established in vitro model for pseudofollicles. Leukemia 2009; 23: 2118–2128.

    Article  CAS  PubMed  Google Scholar 

  59. Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS . Ibrutinib therapy increases BCL-2 dependence and enhances sensitivity to venetoclax in CLL. Blood 2015; 126: 490–490.

    Google Scholar 

  60. 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 2012; 30: 488–496.

    Article  CAS  PubMed  Google Scholar 

  61. 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.

    Article  CAS  PubMed  Google Scholar 

  62. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016; 374: 311–322.

    Article  CAS  PubMed  Google Scholar 

  63. Faia K, White K, Proctor J, Andrade P, Pink M, Rickles R et al. High throughput in vitro combination sensitivity screen in hematologic malignancies with the phosphoinositide-3 kinase (PI3K)-{delta},{gamma} inhibitor, duvelisib. ASCO Meeting Abstracts 2015; 33 (15_suppl): 8559.

    Google Scholar 

  64. Pepper C, Lin TT, Pratt G, Hewamana S, Brennan P, Hiller L et al. Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers. Blood 2008; 112: 3807–3817.

    Article  CAS  PubMed  Google Scholar 

  65. Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 2016; 17: 768–778.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ben Hayes and Mark Nelson to coordinate patient sample distribution, and Yuling Chen and Min Fu for patient sample collection. This work was supported in part by grant P01CA81534 and cancer center core grant CA16672 from the NCI, DHHS, a sponsored research agreement from Infinity Pharmaceuticals, Inc., and funds from the MD Anderson Moon Shot Program.

Author contributions

VKP designed and performed most of the experiments presented in this study, analyzed data and wrote the manuscript. KB directed VKP, performed some experiments and helped with writing of the manuscript. MD, TT, EYX performed RNASeq and Nanostring experiments. HMS, JK directed worked done at Infinity and reviewed the manuscript. MA performed all immunoblots. AS, RG performed some experiments. WGW, SO, NJ were conducting clinical trials, provided clinical and patient-related information. VG obtained funding, participated in designing experiments and reviewed the manuscript.

Author information

Author notes

  1. E Y Xu

    Present address: 4Current address: Sanofi Genzyme, Framingham, MA 01701, USA.,

Authors and Affiliations

  1. Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    V M Patel, K Balakrishnan, M Ayers, A Sarkar, R Guerrieri & V Gandhi

  2. Infinity Pharmaceuticals Inc., Cambridge, MA, USA

    M Douglas, T Tibbitts, E Y Xu, J L Kutok & H M Stern

  3. Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    W G Wierda, S O'Brien, N Jain & V Gandhi

Authors
  1. V M Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Balakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Douglas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Tibbitts
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Y Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J L Kutok
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Ayers
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Sarkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R Guerrieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. W G Wierda
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S O'Brien
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. N Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. H M Stern
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. V Gandhi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V Gandhi.

Ethics declarations

Competing interests

KB/VG received sponsored research agreement from Infinity Pharmaceuticals, Inc. MD, TT, EYX, JLK, HMS are employees and shareholders of Infinity Pharmaceuticals, Inc. The remaining authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patel, V., Balakrishnan, K., Douglas, M. et al. Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199). Leukemia 31, 1872–1881 (2017). https://doi.org/10.1038/leu.2016.382

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2016.382

This article is cited by

Search

Advanced search

Quick links