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.

Acute myeloid leukemia

The CD33 splice isoform lacking exon 2 as therapeutic target in human acute myeloid leukemia

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Cell surface characterization of human acute leukemia cells with anti-CD33∆E2 antibodies.
Fig. 2: Whole cell characterization of human acute leukemia cells with anti-CD33∆E2 antibodies.

References

  1. 1.

    Grossbard ML, Press OW, Appelbaum FR, Bernstein ID, Nadler LM. Monoclonal antibody-based therapies of leukemia and lymphoma. Blood. 1992;80:863–78.

    CAS  Article  Google Scholar 

  2. 2.

    Walter RB, Appelbaum FR, Estey EH, Bernstein ID. Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood. 2012;119:6198–208.

    CAS  Article  Google Scholar 

  3. 3.

    Laszlo GS, Estey EH, Walter RB. The past and future of CD33 as therapeutic target in acute myeloid leukemia. Blood Rev. 2014;28:143–53.

    CAS  Article  Google Scholar 

  4. 4.

    Godwin CD, Gale RP, Walter RB. Gemtuzumab ozogamicin in acute myeloid leukemia. Leukemia. 2017;31:1855–68.

    CAS  Article  Google Scholar 

  5. 5.

    Walter RB. Investigational CD33-targeted therapeutics for acute myeloid leukemia. Exp Opin Investig Drugs. 2018;27:339–48.

    CAS  Article  Google Scholar 

  6. 6.

    Laszlo GS, Harrington KH, Gudgeon CJ, Beddoe ME, Fitzgibbon MP, Ries RE, et al. Expression and functional characterization of CD33 transcript variants in human acute myeloid leukemia. Oncotarget. 2016;7:43281–94.

    Article  Google Scholar 

  7. 7.

    Malik M, Simpson JF, Parikh I, Wilfred BR, Fardo DW, Nelson PT, et al. CD33 Alzheimer’s risk-altering polymorphism, CD33 expression, and exon 2 splicing. J Neurosci. 2013;33:13320–5.

    CAS  Article  Google Scholar 

  8. 8.

    Raj T, Ryan KJ, Replogle JM, Chibnik LB, Rosenkrantz L, Tang A, et al. CD33: increased inclusion of exon 2 implicates the Ig V-set domain in Alzheimer’s disease susceptibility. Hum Mol Genet. 2014;23:2729–36.

    CAS  Article  Google Scholar 

  9. 9.

    Lamba JK, Chauhan L, Shin M, Loken MR, Pollard JA, Wang YC, et al. CD33 splicing polymorphism determines gemtuzumab ozogamicin response in de novo acute myeloid leukemia: report from randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2017;35:2674–82.

    CAS  Article  Google Scholar 

  10. 10.

    Correnti CE, Laszlo GS, de van der Schueren WJ, Godwin CD, Bandaranayake A, Busch MA, et al. Simultaneous multiple interaction T-cell engaging (SMITE) bispecific antibodies overcome bispecific T-cell engager (BiTE) resistance via CD28 co-stimulation. Leukemia. 2018;32:1239–43.

    CAS  Article  Google Scholar 

  11. 11.

    Siddiqui SS, Springer SA, Verhagen A, Sundaramurthy V, Alisson-Silva F, Jiang W, et al. The Alzheimer’s disease-protective CD33 splice variant mediates adaptive loss of function via diversion to an intracellular pool. J Biol Chem. 2017;292:15312–20.

    CAS  Article  Google Scholar 

  12. 12.

    Humbert O, Laszlo GS, Sichel S, Ironside C, Haworth KG, Bates OM, et al. Engineering resistance to CD33-targeted immunotherapy in normal hematopoiesis by CRISPR/Cas9-deletion of CD33 exon 2. Leukemia. 2019;33:762–808.

    Article  Google Scholar 

  13. 13.

    Stewart RS, Drisaldi B, Harris DA. A transmembrane form of the prion protein contains an uncleaved signal peptide and is retained in the endoplasmic Reticulum. Mol Biol Cell. 2001;12:881–9.

    CAS  Article  Google Scholar 

  14. 14.

    Yamamoto K, Hayashishita M, Minami S, Suzuki K, Hagiwara T, Noguchi A, et al. Elimination of a signal sequence-uncleaved form of defective HLA protein through BAG6. Sci Rep. 2017;7:14545.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Dr. Derek L. Stirewalt and Era Pogosova-Agadjanyan for provision of primary human AML specimens from the Fred Hutchinson Cancer Research Center/University of Washington Hematopoietic Diseases Repository. Research reported in this publication was supported by the Leukemia & Lymphoma Society (Translational Research Program, grant 6489–16) and the National Institutes of Health/National Cancer Institute (NIH/NCI) (R21-CA234203, P30-CA015704, and P50-CA100632 [MD Anderson Cancer Center Leukemia SPORE]). C.D.G. is supported by a fellowship training grant from the NIH/National Heart, Lung, and Blood Institute (NHLBI; T32-HL007093), an institutional K12 grant from the NIH/NCI (K12-CA076930) an American Society of Clinical Oncology/Conquer Cancer Foundation Young Investigator Award and an Alex’s Lemonade Stand Young Investigator Grant.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Roland B. Walter.

Ethics declarations

Conflict of interest

HPK is a consultant to and has ownership interests with Rocket Pharma and Homology Medicines and is a consultant to CSL Behring and Magenta Therapeutics. RBW received laboratory research grants and/or clinical trial support from Agios, Amgen, Aptevo Therapeutics, Arog, BioLineRx, Jazz, Pfizer, Seattle Genetics, and Selvita; has ownership interests with Amphivena Therapeutics; and is (or has been) a consultant to Agios, Amphivena Therapeutics, Astellas, BiVictrix, Boehringer Ingelheim, Covagen, Emergent Biosolutions/Aptevo Therapeutics, Jazz, Kite, Pfizer, and Seattle Genetics. The other authors declare no competing financial 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

Verify currency and authenticity via CrossMark

Cite this article

Godwin, C.D., Laszlo, G.S., Wood, B.L. et al. The CD33 splice isoform lacking exon 2 as therapeutic target in human acute myeloid leukemia. Leukemia 34, 2479–2483 (2020). https://doi.org/10.1038/s41375-020-0755-7

Download citation

Further reading

Search

Quick links