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.

  • Article
  • Published:

Acute myeloid leukemia

Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia

Leukemia volume 35, pages 1907–1924 (2021)Cite this article

Subjects

Abstract

Complex karyotype acute myeloid leukemia (CK-AML) has a dismal outcome with current treatments, underscoring the need for new therapies. Here, we report synergistic anti-leukemic activity of the BCL-2 inhibitor venetoclax (Ven) and the asparaginase formulation Pegylated Crisantaspase (PegC) in CK-AML in vitro and in vivo. Ven-PegC combination inhibited growth of multiple AML cell lines and patient-derived primary CK-AML cells in vitro. In vivo, Ven-PegC showed potent reduction of leukemia burden and improved survival, compared with each agent alone, in a primary patient-derived CK-AML xenograft. Superiority of Ven-PegC, compared to single drugs, and, importantly, the clinically utilized Ven-azacitidine combination, was also demonstrated in vivo in CK-AML. We hypothesized that PegC-mediated plasma glutamine depletion inhibits 4EBP1 phosphorylation, decreases the expression of proteins such as MCL-1, whose translation is cap dependent, synergizing with the BCL-2 inhibitor Ven. Ven-PegC treatment decreased cellular MCL-1 protein levels in vitro by enhancing eIF4E-4EBP1 interaction on the cap-binding complex via glutamine depletion. In vivo, Ven-PegC treatment completely depleted plasma glutamine and asparagine and inhibited mRNA translation and cellular protein synthesis. Since this novel mechanistically-rationalized regimen combines two drugs already in use in acute leukemia treatment, we plan a clinical trial of the Ven-PegC combination in relapsed/refractory CK-AML.

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

Fig. 1: In vitro anti-AML activity of the combination of Ven and PegC.
Fig. 2: Efficacy of Ven, PegC and Ven-PegC combination in an orthotopic patient-derived xenograft (PDX) model of relapsed AML with complex karyotype.
Fig. 3: Efficacy of single agents Ven, PegC, azacitidine (Aza), and combination of Aza-Ven and Ven-PegC in U937-luc cells.
Fig. 4: Alteration of gene transcription in AML after treatment with Ven, PegC, and Ven-PegC.
Fig. 5: Ven-PegC impedes cap-dependent translation and protein synthesis.
Fig. 6: Ven-PegC impedes cap-dependent translation and protein synthesis.
Fig. 7: Effect of Ven-PegC on plasma amino acid levels in vivo in AML45-luc.
Fig. 8: Pharmacodynamic (PD) effects of Ven-PegC in vivo in AML45-luc.

Similar content being viewed by others

References

  1. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075–83.

    Article  CAS  PubMed  Google Scholar 

  2. Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood. 2002;100:4325–36.

    Article  CAS  PubMed  Google Scholar 

  3. Ciurea SO, Labopin M, Socie G, Volin L, Passweg J, Chevallier P, et al. Relapse and survival after transplantation for complex karyotype acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and the University of Texas MD Anderson Cancer Center. Cancer. 2018;124:2134–41.

    Article  CAS  PubMed  Google Scholar 

  4. Schoch C, Kern W, Kohlmann A, Hiddemann W, Schnittger S, Haferlach T. Acute myeloid leukemia with a complex aberrant karyotype is a distinct biological entity characterized by genomic imbalances and a specific gene expression profile. Genes Chromosomes Cancer. 2005;43:227–38.

    Article  CAS  PubMed  Google Scholar 

  5. Kuykendall A, Duployez N, Boissel N, Lancet JE, Welch JS. Acute myeloid leukemia: the good, the bad, and the ugly. Am Soc Clin Oncol Educ Book. 2018;38:555–73.

    Article  PubMed  Google Scholar 

  6. Grzmil M, Hemmings BA. Translation regulation as a therapeutic target in cancer. Cancer Res. 2012;72:3891–900.

    Article  CAS  PubMed  Google Scholar 

  7. 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;19:202–8.

    Article  CAS  PubMed  Google Scholar 

  8. FDA. Venetoclax (Venclexta). Food and Drug Administration; 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208573s208013lbl.pdf.

  9. DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133:7–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Winters AC, Gutman JA, Purev E, Nakic M, Tobin J, Chase S, et al. Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia. Blood Adv. 2019;3:2911–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. DiNardo CD, Rausch CR, Benton C, Kadia T, Jain N, Pemmaraju N, et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol. 2018;93:401–7.

    Article  CAS  PubMed  Google Scholar 

  12. Daneshbod Y, Kohan L, Taghadosi V, Weinberg OK, Arber DA. Prognostic significance of complex karyotypes in acute myeloid leukemia. Curr Treat options Oncol. 2019;20:15.

    Article  PubMed  Google Scholar 

  13. Willems L, Jacque N, Jacquel A, Neveux N, Maciel TT, Lambert M, et al. Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia. Blood. 2013;122:3521–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Emadi A, Jun SA, Tsukamoto T, Fathi AT, Minden MD, Dang CV. Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. Exp Hematol. 2014;42:247–51.

    Article  CAS  PubMed  Google Scholar 

  15. Beckett A, Gervais D. What makes a good new therapeutic L-asparaginase? World J Microbiol Biotechnol. 2019;35:152.

    Article  PubMed  CAS  Google Scholar 

  16. Moola ZB, Scawen MD, Atkinson T, Nicholls DJ. Erwinia chrysanthemi L-asparaginase: epitope mapping and production of antigenically modified enzymes. Biochemical J. 1994;302:921–7.

    Article  CAS  Google Scholar 

  17. Emadi A, Zokaee H, Sausville EA. Asparaginase in the treatment of non-ALL hematologic malignancies. Cancer Chemother Pharmacol. 2014;73:875–83.

    Article  CAS  PubMed  Google Scholar 

  18. Emadi A, Law JY, Strovel ET, Lapidus RG, Jeng LJB, Lee M, et al. Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia. Cancer Chemother Pharmacol. 2018;81:217–22.

    Article  CAS  PubMed  Google Scholar 

  19. Rau RE, Dreyer Z, Choi MR, Liang W, Skowronski R, Allamneni KP, et al. Outcome of pediatric patients with acute lymphoblastic leukemia/lymphoblastic lymphoma with hypersensitivity to pegaspargase treated with PEGylated Erwinia asparaginase, pegcrisantaspase: A report from the Children’s Oncology Group. Pediatric Blood Cancer. 2018;65:e26873.

    Article  CAS  Google Scholar 

  20. Jacque N, Ronchetti AM, Larrue C, Meunier G, Birsen R, Willems L. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood. 2015;126:1346–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bajpai R, Matulis SM, Wei C, Nooka AK, Von Hollen HE, Lonial S, et al. Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax. Oncogene. 2016;35:3955–64.

    Article  CAS  PubMed  Google Scholar 

  22. Chang WK, Yang KD, Chuang H, Jan JT, Shaio MF. Glutamine protects activated human T cells from apoptosis by up-regulating glutathione and Bcl-2 levels. Clin Immunol. 2002;104:151–60.

    Article  CAS  PubMed  Google Scholar 

  23. Nguyen HA, Su Y, Zhang JY, Antanasijevic A, Caffrey M, Schalk AM, et al. A novel l-asparaginase with low l-glutaminase coactivity is highly efficacious against both T- and B-cell acute lymphoblastic leukemias in vivo. Cancer Res. 2018;78:1549–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. van der Sluis IM, Vrooman LM, Pieters R, Baruchel A, Escherich G, Goulden N, et al. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica. 2016;101:279–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Chien WW, Allas S, Rachinel N, Sahakian P, Julien M, Le Beux C, et al. Pharmacology, immunogenicity, and efficacy of a novel pegylated recombinant Erwinia chrysanthemi-derived L-asparaginase. Invest New Drugs. 2014;32:795–805.

    Article  CAS  PubMed  Google Scholar 

  26. Campos EDV, Pinto R. Targeted therapy with a selective BCL-2 inhibitor in older patients with acute myeloid leukemia. Hematol Transfus Cell Ther. 2019;41:169–77.

    Article  PubMed  Google Scholar 

  27. Emadi A, Bade NA, Stevenson B, Singh Z. Minimally-myelosuppressive asparaginase-containing induction regimen for treatment of a Jehovah’s witness with mutant IDH1/NPM1/NRAS Acute Myeloid Leukemia. Pharmaceuticals. 2016;9:12.

    Article  PubMed Central  CAS  Google Scholar 

  28. Bade NA, Lu C, Patzke CL, Baer MR, Duong VH, Law JY, et al. Optimizing pegylated asparaginase use: an institutional guideline for dosing, monitoring, and management. J Oncol Pharm Pract. 2020;26:74–92.

    Article  CAS  PubMed  Google Scholar 

  29. Liu WJ, Wang H, Peng XW, Wang WD, Liu NW, Wang Y, et al. Asparagine synthetase expression is associated with the sensitivity to asparaginase in extranodal natural killer/T-cell lymphoma in vivo and in vitro. Onco Targets Ther. 2018;11:6605–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chigaev A. Does aberrant membrane transport contribute to poor outcome in adult acute myeloid leukemia? Front Pharm. 2015;6:134.

    Article  CAS  Google Scholar 

  31. Federzoni EA, Humbert M, Torbett BE, Behre G, Fey MF, Tschan MP. CEBPA-dependent HK3 and KLF5 expression in primary AML and during AML differentiation. Sci Rep. 2014;4:4261.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Nunes-Xavier C, Roma-Mateo C, Rios P, Tarrega C, Cejudo-Marin R, Tabernero L, et al. Dual-specificity MAP kinase phosphatases as targets of cancer treatment. Anti-cancer agents medicinal Chem. 2011;11:109–32.

    Article  CAS  Google Scholar 

  33. Elf S, Blevins D, Jin L, Chung TW, Williams IR, Lee BH, et al. p90RSK2 is essential for FLT3-ITD- but dispensable for BCR-ABL-induced myeloid leukemia. Blood. 2011;117:6885–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mirabilii S, Ricciardi MR, Piedimonte M, Gianfelici V, Bianchi MP, Tafuri A. Biological aspects of mTOR in Leukemia. Int J Mol Sci. 2018;19:2396.

    Article  PubMed Central  CAS  Google Scholar 

  35. Choudhary GS, Al-Harbi S, Mazumder S, Hill BT, Smith MR, Bodo J. et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6:e1593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Carroll M, Borden KL. The oncogene eIF4E: using biochemical insights to target cancer. J Interferon Cytokine Res. 2013;33:227–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hay N. Mnk earmarks eIF4E for cancer therapy. Proc Natl Acad Sci USA. 2010;107:13975–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kapadia B, Nanaji NM, Bhalla K, Bhandary B, Lapidus R, Beheshti A, et al. Fatty Acid Synthase induced S6Kinase facilitates USP11-eIF4B complex formation for sustained oncogenic translation in DLBCL. Nat Commun. 2018;9:829.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a Phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6:1106–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bodo J, Zhao X, Durkin L, Souers AJ, Phillips DC, Smith MR, et al. Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells. Oncotarget. 2016;7:70000–10.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tahir SK, Smith ML, Hessler P, Rapp LR, Idler KB, Park CH, et al. Potential mechanisms of resistance to venetoclax and strategies to circumvent it. BMC Cancer. 2017;17:399.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A. BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell. 2007;12:171–85.

    Article  CAS  PubMed  Google Scholar 

  43. Yecies D, Carlson NE, Deng J, Letai A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood. 2010;115:3304–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Guieze R, Liu VM, Rosebrock D, Jourdain AA, Hernandez-Sanchez M, Martinez Zurita A, et al. Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies. Cancer Cell. 2019;36:369–84.e313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Opferman JT, Iwasaki H, Ong CC, Suh H, Mizuno S, Akashi K, et al. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science. 2005;307:1101–4.

    Article  CAS  PubMed  Google Scholar 

  46. Vick B, Weber A, Urbanik T, Maass T, Teufel A, Krammer PH, et al. Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes. Hepatology. 2009;49:627–36.

    Article  CAS  PubMed  Google Scholar 

  47. Thomas RL, Roberts DJ, Kubli DA, Lee Y, Quinsay MN, Owens JB, et al. Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure. Genes Dev. 2013;27:1365–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wendel HG, Silva RL, Malina A, Mills JR, Zhu H, Ueda T, et al. Dissecting eIF4E action in tumorigenesis. Genes Dev. 2007;21:3232–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926–45.

    Article  CAS  PubMed  Google Scholar 

  50. Le Gouill S, Podar K, Harousseau JL, Anderson KC. Mcl-1 regulation and its role in multiple myeloma. Cell Cycle. 2004;3:1259–62.

    Article  PubMed  Google Scholar 

  51. Rahmani M, Davis EM, Bauer C, Dent P, Grant S. Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem. 2005;280:35217–27.

    Article  CAS  PubMed  Google Scholar 

  52. Tang R, Faussat AM, Majdak P, Marzac C, Dubrulle S, Marjanovic Z, et al. Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells. Mol Cancer Ther. 2006;5:723–31.

    Article  CAS  PubMed  Google Scholar 

  53. Stolzel F, Mohr B, Kramer M, Oelschlagel U, Bochtler T, Berdel WE, et al. Karyotype complexity and prognosis in acute myeloid leukemia. Blood Cancer J. 2016;6:e386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul. 1984;22:27–55.

    Article  CAS  Google Scholar 

  55. Shetty AC, Adkins RS, Chatterjee A, McCracken CL, Hodges T, Creasy HH, et al. CAVERN: Computational and visualization environment for RNA-seq analyses. In: Proceedings of the 69th Annual Meeting American Society of Human Genetics; 2019.

  56. Andrews S FastQC A. Quality control tool for high throughput sequence data. http://www.bioinformaticsbabrahamacuk/projects/fastqc/ 2010.

  57. Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12:357–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Anders S, Pyl PT, Huber W. HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.

    Article  CAS  PubMed  Google Scholar 

  59. Anders S, Huber W. Differential expression analysis for sequence count data. Genome Biol. 2010;11:R106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Ying Zou, MD, PhD, Nicholas Ambulos, PhD and Danielle Sewell, MSRS of the Genomics Shared Service of University of Maryland School of Medicine for validating the cell lines by short tandem repeat analysis and karyotyping them. We thank Xiaoxuan Fan, PhD and Bryan Hahn, BS of the Flow Cytometry Shared Service at UMGCCC for helping to sort the YFP-positive cells after transduction and the Center for Translational Research in Imaging for access to Xenogen. The CRISPR Core at UMGCCC packaged the plasmid into lentiviruses.

Funding

This study was supported by a research grant provided by Jazz Pharmaceuticals to AE. This work was partially supported by the University of Maryland Greenebaum Comprehensive Cancer Center Support grant (P30CA134274) and the State of Maryland’s Cigarette Restitution Funds.

Author information

Author notes

  1. Bandish Kapadia & Ronald B. Gartenhaus

    Present address: Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, USA

Authors and Affiliations

  1. University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA

    Ashkan Emadi, Bandish Kapadia, Dominique Bollino, Binny Bhandary, Maria R. Baer, Sandrine Niyongere, Elizabeth Chang, Eun Yong Choi, Xinrong Ma, Kayla M. Tighe, Brandon Carter-Cooper, Curt I. Civin, Anup Mahurkar, Amol C. Shetty, Ronald B. Gartenhaus & Rena G. Lapidus

  2. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Ashkan Emadi, Dominique Bollino, Maria R. Baer, Sandrine Niyongere, Hannah Kaizer, Ronald B. Gartenhaus & Rena G. Lapidus

  3. Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA

    Ashkan Emadi

  4. Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA

    Erin T. Strovel, Blake S. Moses & Curt I. Civin

  5. University of Maryland Center for Stem Cell Biology & Regenerative Medicine, Baltimore, MD, USA

    Blake S. Moses & Curt I. Civin

  6. Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Curt I. Civin

  7. Institute of Genome Sciences, University of Maryland, Baltimore, MD, USA

    Anup Mahurkar & Amol C. Shetty

  8. Department of Biology, School of Computer, Mathematical, and Natural Sciences, Morgan State University, Baltimore, MD, USA

    Farin Kamangar

Authors
  1. Ashkan Emadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bandish Kapadia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dominique Bollino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Binny Bhandary
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria R. Baer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sandrine Niyongere
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Erin T. Strovel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hannah Kaizer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elizabeth Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Eun Yong Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xinrong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kayla M. Tighe
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Brandon Carter-Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Blake S. Moses
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Curt I. Civin
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Anup Mahurkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Amol C. Shetty
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Ronald B. Gartenhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Farin Kamangar
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Rena G. Lapidus
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AE conceived the idea, conceptualized the hypotheses, and designed and supervised all areas of the study. AE, BK, AS, RBG, and RGL designed experiments and developed the methodology. AE, BK, DB, AS, FK, and RGL analyzed and interpreted the data. BK, BB, DB, HK, BC-C, and BSM performed in vitro studies with cell lines and primary cells including transduction of cells. EC, EYC, XM, KMT, and RGL carried out in vivo experiments under IACUC protocols. AM and AS performed the RNA-seq experiments related to transcriptome and translatome. BK performed Western blot and qPCR for mechanistic studies. ETS performed plasma amino acid analysis. FK conducted all the statistical analysis for the in vivo and amino acid analysis studies. AE, BK, and RGL wrote, reviewed, and revised the first draft of the manuscript. SN, MRB, and CIC contributed to preparing and writing the manuscript.

Corresponding author

Correspondence to Ashkan Emadi.

Ethics declarations

Conflict of interest

AE has received research grants from Jazz Pharmaceuticals and NewLink Genetics. AE is a global oncology advisory board member for Amgen and has served as an advisory board member for Genentech and Servier. AE and RGL are Co-Founders and Scientific Advisors for KinaRx, LLC. All other authors declare that they have no relevant competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Emadi, A., Kapadia, B., Bollino, D. et al. Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia. Leukemia 35, 1907–1924 (2021). https://doi.org/10.1038/s41375-020-01080-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-020-01080-6

This article is cited by

Search

Advanced search

Quick links