Skip to main content

Advertisement

SpringerLink
Log in

All-trans retinoic acid induces differentiation in primary acute myeloid leukemia blasts carrying an inversion of chromosome 16

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

All-trans retinoic acid (ATRA)-based therapy for acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), is the most successful example of differentiation therapy. Although ATRA can induce differentiation in some non-APL AML cell lines and primary blasts, clinical results of adding ATRA to standard therapy in non-APL AML patients have been inconsistent, probably due to use of different regimens and lack of diagnostic tools for identifying which patients may be sensitive to ATRA. In this study, we exposed primary blasts obtained from non-APL AML patients to ATRA to test for differentiation potential in vitro. We observed increased expression of differentiation markers, indicating a response to ATRA, in four out of fifteen primary AML samples. Three samples in which CD11b increased in response to ATRA had an inversion of chromosome 16 as well as the CBFB-MYH11 fusion gene, and the fourth sample was from a patient with KMT2A-rearranged, therapy-related AML. In conclusion, we identified a subgroup of non-APL AML patients with inv(16) and CBFB-MYH11 as the most sensitive to ATRA-mediated differentiation in vitro, and our results can help identify patients who may benefit from ATRA treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Short NJ, Konopleva M, Kadia TM, Borthakur G, Ravandi F, DiNardo CD, Daver N. Advances in the treatment of acute myeloid leukemia: new drugs and new challenges. Cancer Discov. 2020;10:506–25. https://doi.org/10.1158/2159-8290.CD-19-1011.

    Article  CAS  PubMed  Google Scholar 

  2. Breitman TR, Selonick SE, Collins SJ. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci. 1980;77:2936–40. https://doi.org/10.1073/pnas.77.5.2936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nguyen CH, Grandits AM, Purton LE, Sill H, Wieser R. All-trans retinoic acid in non-promyelocytic acute myeloid leukemia: driver lesion dependent effects on leukemic stem cells. Cell Cycle. 2020;19:2573–88. https://doi.org/10.1080/15384101.2020.1810402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. di Martino O, Welch JS. Retinoic acid receptors in acute myeloid leukemia therapy. Cancers. 2019. https://doi.org/10.3390/cancers11121915.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Pan P, Chen X. Nuclear receptors as potential therapeutic targets for myeloid leukemia. Cells. 2020. https://doi.org/10.3390/cells9091921.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Milligan DW, Wheatley K, Littlewood T, Craig JIO, Burnett AK. Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial. Blood. 2006;107:4614–22. https://doi.org/10.1182/blood-2005-10-4202.

    Article  CAS  PubMed  Google Scholar 

  7. Burnett AK, Hills RK, Green C, Jenkinson S, Koo K, Patel Y, Guy C, Gilkes A, Milligan DW, Goldstone AH, et al. The impact on outcome of the addition of all-trans retinoic acid to intensive chemotherapy in younger patients with nonacute promyelocytic acute myeloid leukemia: overall results and results in genotypic subgroups defined by mutations in NPM1, FLT3, and C. Blood. 2010;115:948–56. https://doi.org/10.1182/blood-2009-08-236588.

    Article  CAS  PubMed  Google Scholar 

  8. Schlenk RF, Dohner K, Kneba M, Gotze K, Hartmann F, del Valle F, Kirchen H, Koller E, Fischer JT, Bullinger L, et al. Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B. Haematologica. 2009;94:54–60. https://doi.org/10.3324/haematol.13378.

    Article  CAS  PubMed  Google Scholar 

  9. Schlenk RF, Lübbert M, Benner A, Lamparter A, Krauter J, Herr W, Martin H, Salih HR, Kündgen A, Horst H-A, et al. All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: results of the randomized AMLSG 07–04 study. Ann Hematol. 2016;95:1931–42. https://doi.org/10.1007/s00277-016-2810-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47. https://doi.org/10.1182/blood-2016-08-733196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bolis M, Terao M, Pattini L, Garattini E, Fratelli M. The ATRA-21 gene-expression model predicts retinoid sensitivity in CEBPA double mutant, t(8;21) and inv(16) AML patients. Blood Cancer J. 2019;9:76. https://doi.org/10.1038/s41408-019-0241-5.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Sykes DB, Kfoury YS, Mercier FE, Wawer MJ, Law JM, Haynes MK, Lewis TA, Schajnovitz A, Jain E, Lee D, et al. Inhibition of dihydroorotate dehydrogenase overcomes differentiation blockade in acute myeloid leukemia. Cell. 2016;167:171-186.e15. https://doi.org/10.1016/j.cell.2016.08.057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. U.S. National Library of Medicine. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=AML&term=DHODH&cntry=&state=&city=&dist=. Accessed 8 Jan 2020

  14. Lalic H, Dembitz V, Lukinovic-Skudar V, Banfic H, Visnjic D. 5-Aminoimidazole-4-carboxamide ribonucleoside induces differentiation of acute myeloid leukemia cells. Leuk Lymphoma. 2014;55:2375–83. https://doi.org/10.3109/10428194.2013.876633.

    Article  CAS  PubMed  Google Scholar 

  15. Dembitz V, Tomic B, Kodvanj I, Simon JA, Bedalov A, Visnjic D. The ribonucleoside AICAr induces differentiation of myeloid leukemia by activating the ATR/Chk1 via pyrimidine depletion. J Biol Chem. 2019;294:15257–70. https://doi.org/10.1074/jbc.RA119.009396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dembitz V, Lalic H, Kodvanj I, Tomic B, Batinic J, Dubravcic K, Batinic D, Bedalov A, Visnjic D. 5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts. BMC Cancer. 2020;20:1090. https://doi.org/10.1186/s12885-020-07533-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Boutzen H, Saland E, Larrue C, de Toni F, Gales L, Castelli FA, Cathebas M, Zaghdoudi S, Stuani L, Kaoma T, et al. Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia. J Exp Med. 2016;213:483–97. https://doi.org/10.1084/jem.20150736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ma HS, Greenblatt SM, Shirley CM, Duffield AS, Bruner JK, Li L, Nguyen B, Jung E, Aplan PD, Ghiaur G, et al. All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo. Blood. 2016;127:2867–78. https://doi.org/10.1182/blood-2015-05-646786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhou J, Yiying Quah J, Ng Y, Chooi J-Y, Hui-Min Toh S, Lin B, Zea Tan T, Hosoi H, Osato M, Seet Q, et al. ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia. Haematologica. 2020;105:2286–97. https://doi.org/10.3324/haematol.2019.230482.

    Article  CAS  PubMed  Google Scholar 

  20. Qian S-X, Li J, Hong M, Qiu H-R, Fan L, Xu W. Acute myeloid leukemia in four patients with t(8;21) treated with all-trans retinoic acid as a single agent. Leuk Lymphoma. 2008;49:998–1001. https://doi.org/10.1080/10428190801959018.

    Article  PubMed  Google Scholar 

  21. El Hajj H, Dassouki Z, Berthier C, Raffoux E, Ades L, Legrand O, Hleihel R, Sahin U, Tawil N, Salameh A, et al. Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells. Blood. 2015;125:3447–54. https://doi.org/10.1182/blood-2014-11-612416.

    Article  CAS  PubMed  Google Scholar 

  22. Martelli MP, Gionfriddo I, Mezzasoma F, Milano F, Pierangeli S, Mulas F, Pacini R, Tabarrini A, Pettirossi V, Rossi R, et al. Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells. Blood. 2015;125:3455–65. https://doi.org/10.1182/blood-2014-11-611459.

    Article  CAS  PubMed  Google Scholar 

  23. Opatz S, Bamopoulos SA, Metzeler KH, Herold T, Ksienzyk B, Bräundl K, Tschuri S, Vosberg S, Konstandin NP, Wang C, et al. The clinical mutatome of core binding factor leukemia. Leukemia. 2020;34:1553–62. https://doi.org/10.1038/s41375-019-0697-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. di Martino O, Niu H, Hadwiger G, Kuusanmaki H, Ferris MA, Vu A, Beales J, Wagner C, Menéndez-Gutiérrez MP, Ricote M, et al. Endogenous and combination retinoids are active in myelomonocytic leukemias. Haematologica. 2021;106:1008–21. https://doi.org/10.3324/haematol.2020.264432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nguyen CH, Grandits AM, Vassiliou GS, Staber PB, Heller G, Wieser R. Evi1 counteracts anti-leukemic and stem cell inhibitory effects of all-trans retinoic acid on Flt3-ITD/Npm1c-driven acute myeloid leukemia cells. Biomed. 2020. https://doi.org/10.3390/biomedicines8100385.

    Article  Google Scholar 

  26. Verhagen HJMP, Smit MA, Rutten A, Denkers F, Poddighe PJ, Merle PA, Ossenkoppele GJ, Smit L. Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid. Blood. 2016;127:458–63. https://doi.org/10.1182/blood-2015-07-653840.

    Article  CAS  PubMed  Google Scholar 

  27. Sakamoto K, Imamura T, Yano M, Yoshida H, Fujiki A, Hirashima Y, Hosoi H. Sensitivity of MLL-rearranged AML cells to all-trans retinoic acid is associated with the level of H3K4me2 in the RARα promoter region. Blood Cancer J. 2014;4:e205–e205. https://doi.org/10.1038/bcj.2014.25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fujiki A, Imamura T, Sakamoto K, Kawashima S, Yoshida H, Hirashima Y, Miyachi M, Yagyu S, Nakatani T, Sugita K, et al. All-trans retinoic acid combined with 5-Aza-2′-deoxycitidine induces C/EBPα expression and growth inhibition in MLL-AF9-positive leukemic cells. Biochem Biophys Res Commun. 2012;428:216–23. https://doi.org/10.1016/j.bbrc.2012.09.131.

    Article  CAS  PubMed  Google Scholar 

  29. Morosetti R, Park DJ, Chumakov AM, Grillier I, Shiohara M, Gombart AF, Nakamaki T, Weinberg K, Koeffler HP. A novel, myeloid transcription factor, C/EBPε, is upregulated during granulocytic, but not monocytic, differentiation. Blood. 1997;90:2591–600. https://doi.org/10.1182/blood.V90.7.2591.

    Article  CAS  PubMed  Google Scholar 

  30. Rethmeier A, Aggerholm A, Olesen LH, Juhl-Christensen C, Nyvold CG, Guldberg P, Hokland P. Promoter hypermethylation of the retinoic acid receptor β2 gene is frequent in acute myeloid leukaemia and associated with the presence of CBFβ–MYH11 fusion transcripts. Br J Haematol. 2006;133:276–83. https://doi.org/10.1111/j.1365-2141.2006.06014.x.

    Article  CAS  PubMed  Google Scholar 

  31. Cao Y, Liu Y, Shang L, Wei W, Shen Y, Gu Q, Xie X, Dong W, Lin Y, Yue Y, et al. Decitabine and all-trans retinoic acid synergistically exhibit cytotoxicity against elderly AML patients via miR-34a/MYCN axis. Biomed Pharmacother. 2020;125: 109878. https://doi.org/10.1016/j.biopha.2020.109878.

    Article  CAS  PubMed  Google Scholar 

  32. Lübbert M, Grishina O, Schmoor C, Schlenk RF, Jost E, Crysandt M, Heuser M, Thol F, Salih HR, Schittenhelm MM, et al. Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 × 2, Phase II Trial. J Clin Oncol. 2019;38:257–70. https://doi.org/10.1200/JCO.19.01053.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Paolo Gallipoli for his support and help with gene expression analysis and Ms Marijana Andrijašević for valuable technical help.

Funding

This work has been funded by Croatian Science Foundation under the projects IP-2016-06-4581, DOK-2018-01-9599 and DOK-2020-01-2873 by the European Union through the ESF Operational Programme Efficient Human Resources 2014–2020 (to D.V.), and co-financed by the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project “Experimental and clinical research of hypoxic-ischemic damage in perinatal and adult brain”; GA KK01.1.1.01.0007) funded by the European Union through the European Regional Development Fund).

Author information

Author notes

  1. Vilma Dembitz and Hrvoje Lalic have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Laboratory of Cell Biology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia

    Vilma Dembitz, Hrvoje Lalic, Barbara Tomic, Tomislav Smoljo & Dora Visnjic

  2. Department of Physiology, School of Medicine, University of Zagreb, Salata 3, 10 000, Zagreb, Croatia

    Vilma Dembitz, Hrvoje Lalic, Barbara Tomic, Tomislav Smoljo, Drago Batinic & Dora Visnjic

  3. Division of Hematology, Department of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia

    Josip Batinic

  4. Department of Laboratory Immunology, University Hospital Center Zagreb, Zagreb, Croatia

    Klara Dubravcic & Drago Batinic

  5. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Antonio Bedalov

Authors
  1. Vilma Dembitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hrvoje Lalic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barbara Tomic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomislav Smoljo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Josip Batinic
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Klara Dubravcic
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Drago Batinic
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Antonio Bedalov
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dora Visnjic
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

VD collected and analyzed data, performed RT-qPCR and wrote and edited the manuscript; HL collected and analyzed data, performed flow cytometry analyses and wrote and edited the manuscript; BT and TS collected and analyzed data, performed morphological analyses and edited manuscript; JB enrolled and treated patients, collected marrow specimens, and collected data; KD and DB collected marrow specimens, analyzed flow cytometry data and edited the manuscript; AB designed the study, analyzed data, and edited the manuscript; DV designed the study, collected and analyzed data and wrote the manuscript; and all authors critically reviewed the manuscript.

Corresponding author

Correspondence to Dora Visnjic.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

12185_2021_3224_MOESM1_ESM.tif

Supplementary file1 Supplementary Fig. 1. 1 μM ATRA induces differentiation in HL-60, NB-4, MOLM-14, THP-1 and U937 cell lines. Cells were seeded at concentration 0.2x106/mL with or without ATRA for 72 h. In flow cytometric analysis, 7-AAD- cells are represented on FSC/SSC plots in red, and 7-AAD+ cells in black. Histograms are presented from 7-AAD- cells with red line representing isotypic control and blue line representing the expression of CD11b or CD64. Results are a representative experiment of two independent experiments (TIF 970 KB)

Supplementary file2 (DOCX 13 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dembitz, V., Lalic, H., Tomic, B. et al. All-trans retinoic acid induces differentiation in primary acute myeloid leukemia blasts carrying an inversion of chromosome 16. Int J Hematol 115, 43–53 (2022). https://doi.org/10.1007/s12185-021-03224-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-021-03224-5

Keywords

Search

Navigation