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Acute myeloid leukemia

Overcoming microenvironment-mediated protection from ATRA using CYP26-resistant retinoids

Leukemia volume 34, pages 3077–3081 (2020)Cite this article

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The success of all-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL) was one of the important milestones in the fight against cancer, leading to expectations that the therapeutic benefits of differentiation therapy would extend to other types of leukemia and even solid tumors [1]. Although initial clinical trials demonstrated some activity of retinoid therapy against non-APL acute AML [2], subsequent studies failed to replicate these results [3]. Nevertheless, the majority of AML blasts are sensitive to retinoids in vitro [4], although the concentrations of ATRA required to induce differentiation varies greatly, with some leukemia types (APL, NPM1 mutated, IDH mutated, and those expressing an active RARα super-enhancer) being the most sensitive [5, 6]. Even in APL, single agent ATRA induces remissions without cures [7]. In the settings of minimal residual disease (MRD) in APL, the liposomal formulation of ATRA can eliminate MRD and cure about a third of these patients [8] suggesting that pharmacokinetic (PKs) properties of ATRA are at play. The systemic PKs of ATRA are primarily controlled by CYP26, a family of cytochrome P450 monooxygenases responsible for ATRA oxidation and inactivation. The same enzymes are present in bone marrow (BM) mesenchymal stroma cells (MSCs) and by protecting hematopoietic cells from endogenous retinoid maintain their immature phenotype [9]. Plasma retinoid levels are tightly controlled by rapid upregulation of hepatic CYP26A1. It is currently unknown if similar feedback mechanisms are at play in the BM microenvironment but if so, treatment with ATRA may result in paradoxically low retinoid levels in the marrow and thus, “hyperprotective” niches. ATRA signals through one of three retinoic acid receptors (RARs: RARα, RARβ, and RARγ) and these receptors have nonoverlapping functions. We sought to investigate if induction of differentiation and control of local retinoid PKs are differentially regulated by the various RARs.

Given the importance of pharmacodynamics in RAR activity, we next determined which CYP26 isoenzyme contributes to ATRA homeostasis in the BM niche. First, we confirmed the presence of CYP26A1 and CYP26B1 in MSCs (Fig. S3A, C). We found that CYP26B1 was relatively more abundant in these cells compared with hepatocytes, which have been reported to express higher levels of CYP26A1 [12, 13]. CYP26C1 was not detected in MSCs (Fig. S3A, C). RARα, RARβ, and RARγ were all expressed by MSCs, though RARα and RARγ appear more abundant (Fig. S3B, C). In contrast to the previously reported induction of hepatic CYP26A1 in response to ATRA, exposure of MSCs to retinoids induced CYP26B1 (Fig. 1e) but had no effect on CYP26A1 levels (Fig. S4A–C). While all retinoids tested had some measurable effect on CYP26B1 levels (Fig. 1e), the kinetics and the magnitude of CYP26B1 upregulation differed greatly. ATRA, which activates multiple RARs, induced a brisk upregulation of CYP26B1 that fell off after 24 h, consistent with its relatively short half-life of only 7 h [6]. Conversely, AM80 induced a robust upregulation of CYP26B1, which was sustained up to 72 h. Target activation of RARγ via CD437 also had a persistent effect on CYP26B1 levels, while IRX195183, which exclusively activates RARα, had only a minimal effect on CYP26B1 upregulation over a broad range of concentrations (Fig. 1f). Thus, RAR selective synthetic retinoids may have unique properties in the induction of CYP26B1 isoenzymes.

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Fig. 1: The impact of various RAR agonists on differentiation of leukemia cells and on expression of stromal CYP26B1.
Fig. 2: Effects of RARα selective retinoids on differentiation of AML cells in stroma co-culture and xenograft models.

References

  1. Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer. 2001;1:181–93.

    Article  CAS  Google Scholar 

  2. Schlenk RF, Frohling S, Hartmann F, Fischer JT, Glasmacher A, del Valle F, et al. Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia. 2004;18:1798–803.

    Article  CAS  Google Scholar 

  3. Milligan DW, Wheatley K, Littlewood T, Craig JI, Burnett AK, Group NHOCS. 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.

    Article  CAS  Google Scholar 

  4. Ryningen A, Stapnes C, Paulsen K, Lassalle P, Gjertsen BT, Bruserud O. In vivo biological effects of ATRA in the treatment of AML. Expert Opin Investig drugs. 2008;17:1623–33.

    Article  CAS  Google Scholar 

  5. McKeown MR, Corces MR, Eaton ML, Fiore C, Lee E, Lopez JT, et al. Super-enhancer analysis defines novel epigenomic subtypes of non-APL AML including an RARalpha dependency targetable by SY-1425, a potent and selective RARalpha agonist. Cancer Discov. 2017;7:1136–53. https://doi.org/10.1158/2159-8290.CD-17-0399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Su M, Alonso S, Jones JW, Yu J, Kane MA, Jones RJ, et al. All-trans retinoic acid activity in acute myeloid leukemia: role of cytochrome P450 enzyme expression by the microenvironment. PLoS ONE. 2015;10:e0127790.

    Article  Google Scholar 

  7. Warrell RP Jr., Frankel SR, Miller WH Jr., Scheinberg DA, Itri LM, Hittelman WN, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991;324:1385–93.

    Article  Google Scholar 

  8. Tsimberidou AM, Tirado-Gomez M, Andreeff M, O’Brien S, Kantarjian H, Keating M, et al. Single-agent liposomal all-trans retinoic acid can cure some patients with untreated acute promyelocytic leukemia: an update of The University of Texas M. D. Anderson Cancer Center Series. Leuk Lymphoma. 2006;47:1062–8.

    Article  CAS  Google Scholar 

  9. Ghiaur G, Yegnasubramanian S, Perkins B, Gucwa JL, Gerber JM, Jones RJ. Regulation of human hematopoietic stem cell self-renewal by the microenvironment’s control of retinoic acid signaling. Proc Natl Acad Sci USA. 2013;110:16121–6.

    Article  CAS  Google Scholar 

  10. Delescluse C, Cavey MT, Martin B, Bernard BA, Reichert U, Maignan J, et al. Selective high affinity retinoic acid receptor alpha or beta-gamma ligands. Mol Pharmacol. 1991;40:556–62.

    CAS  PubMed  Google Scholar 

  11. Szondy Z, Reichert U, Bernardon JM, Michel S, Toth R, Karaszi E, et al. Inhibition of activation-induced apoptosis of thymocytes by all-trans- and 9-cis-retinoic acid is mediated via retinoic acid receptor alpha. Biochemical J. 1998;331:767–74.

    Article  CAS  Google Scholar 

  12. Owusu SA, Ross AC. Retinoid homeostatic gene expression in liver, lung and kidney: ontogeny and response to vitamin A-retinoic acid (VARA) supplementation from birth to adult age. PLoS ONE. 2016;11:e0145924.

    Article  Google Scholar 

  13. Topletz AR, Thatcher JE, Zelter A, Lutz JD, Tay S, Nelson WL, et al. Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases. Biochemical Pharmacol. 2012;83:149–63.

    Article  CAS  Google Scholar 

  14. Alonso S, Hernandez D, Chang YT, Gocke CB, McCray M, Varadhan R, et al. Hedgehog and retinoid signaling alters multiple myeloma microenvironment and generates bortezomib resistance. J Clin Investig. 2016;126:4460–8.

    Article  Google Scholar 

  15. Alonso S, Jones RJ, Ghiaur G. Retinoic acid, CYP26, and drug resistance in the stem cell niche. Exp Hematol. 2017;54:17–25.

    Article  CAS  Google Scholar 

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Acknowledgements

The project was by enlarged funded by K08 HL127269 (GG), R03 HL145226 (GG), P01CA225618 (BDS, RJJ, GG), and LLS TRP 14086277 (RJJ). LP was covered by T32HL007525 (PI- Robert Brodsky). Quantification of the IRX195183 was performed by the Analytical Pharmacology Core of Johns Hopkins covered by NIH grants P30 CA006973, UL1 TR 001079, and S10RR026824.

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Author notes

  1. Rosh Chandraratna passed away during preparation of the manuscript. Final version was approved on his behalf by Martin Sanders, CEO of IO therapeutics.

Authors and Affiliations

  1. Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, 1650 Orleans St. Room 243, Baltimore, MD, 21231, USA

    Daniela Hernandez, Laura Palau, Kelly Norsworthy, Nicole M. Anders, Salvador Alonso, Meng Su, Michelle A. Rudek, B. Douglas Smith, Richard J. Jones & Gabriel Ghiaur

  2. Cancer Research Institute, Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Martin Petkovich

  3. IO Therapeutics, Santa Ana, CA, USA

    Rosh Chandraratna

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Correspondence to Gabriel Ghiaur.

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SA, RC, RJJ, and GG are authors on a patent application for the use of IRX195183.

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Hernandez, D., Palau, L., Norsworthy, K. et al. Overcoming microenvironment-mediated protection from ATRA using CYP26-resistant retinoids. Leukemia 34, 3077–3081 (2020). https://doi.org/10.1038/s41375-020-0790-4

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