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Molecular targets for therapy

RNA-binding protein IGF2BP1 maintains leukemia stem cell properties by regulating HOXB4, MYB, and ALDH1A1

Leukemia volume 34, pages 1354–1363 (2020)Cite this article

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Abstract

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an oncofetal protein expressed in various cancers including leukemia. In this study, we assessed the role of IGF2BP1 in orchestrating leukemia stem cell properties. Tumor-initiating potential, sensitivity to chemotherapeutic agents, and expression of cancer stem cell markers were assessed in a panel of myeloid, B-, and T-cell leukemia cell lines using gain- and loss-of-function systems, cross-linking immunoprecipitation (CLIP), and photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation (PAR-CLIP) techniques. Here, we report that genetic or chemical inhibition of IGF2BP1 decreases leukemia cells’ tumorigenicity, promotes myeloid differentiation, increases leukemia cell death, and sensitizes leukemia cells to chemotherapeutic drugs. IGF2BP1 affects proliferation and tumorigenic potential of leukemia cells through critical regulators of self-renewal HOXB4 and MYB and through regulation of expression of the aldehyde dehydrogenase, ALDH1A1. Our data indicate that IGF2BP1 maintains leukemia stem cell properties by regulating multiple pathways of stemness through transcriptional and metabolic factors.

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Data availability

Data used for bioinformatics analysis were deposited in NCBI Gene Expression Omnibus (GEO) repository and can be accessed through the series accession numbers GSE138704 and GSE138063.

References

  1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Pineros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144:1941–53.

    Article  PubMed  CAS  Google Scholar 

  2. de Rooij JD, Zwaan CM, van den Heuvel-Eibrink M. Pediatric AML: from biology to clinical management. J Clin Med. 2015;4:127–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Hernandez-Boluda JC, Pereira A, Pastor-Galan I, Alvarez-Larran A, Savchuk A, Puerta JM, et al. Feasibility of treatment discontinuation in chronic myeloid leukemia in clinical practice: results from a nationwide series of 236 patients. Blood Cancer J. 2018;8:91.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.

    Article  PubMed  CAS  Google Scholar 

  6. Shlush LI, Mitchell A, Heisler L, Abelson S, Ng SWK, Trotman-Grant A, et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. 2017;547:104–8.

    Article  PubMed  CAS  Google Scholar 

  7. Ng SW, Mitchell A, Kennedy JA, Chen WC, McLeod J, Ibrahimova N, et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature. 2016;540:433–7.

    Article  PubMed  CAS  Google Scholar 

  8. Degrauwe N, Suva ML, Janiszewska M, Riggi N, Stamenkovic I. IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer. Genes Dev. 2016;30:2459–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Huang X, Zhang H, Guo X, Zhu Z, Cai H, Kong X. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in cancer. J Hematol Oncol. 2018;11:88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Palanichamy JK, Tran TM, Howard JM, Contreras JR, Fernando TR, Sterne-Weiler T, et al. RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation. J Clin Investig. 2016;126:1495–511.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zhou J, Bi C, Ching YQ, Chooi JY, Lu X, Quah JY, et al. Inhibition of LIN28B impairs leukemia cell growth and metabolism in acute myeloid leukemia. J Hematol Oncol. 2017;10:138.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Mark Welch DB, Jauch A, Langowski J, Olins AL, Olins DE. Transcriptomes reflect the phenotypes of undifferentiated, granulocyte and macrophage forms of HL-60/S4 cells. Nucleus. 2017;8:222–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Olins AL, Buendia B, Herrmann H, Lichter P, Olins DE. Retinoic acid induction of nuclear envelope-limited chromatin sheets in HL-60. Exp Cell Res. 1998;245:91–104.

    Article  PubMed  CAS  Google Scholar 

  14. Mahapatra L, Andruska N, Mao C, Le J, Shapiro DJ. A novel IMP1 inhibitor, BTYNB, targets c-Myc and inhibits melanoma and ovarian cancer cell proliferation. Transl Oncol. 2017;10:818–27.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Leeds P, Kren BT, Boylan JM, Betz NA, Steer CJ, Gruppuso PA, et al. Developmental regulation of CRD-BP, an RNA-binding protein that stabilizes c-myc mRNA in vitro. Oncogene. 1997;14:1279–86.

    Article  PubMed  CAS  Google Scholar 

  16. Runge S, Nielsen FC, Nielsen J, Lykke-Andersen J, Wewer UM, Christiansen J. H19 RNA binds four molecules of insulin-like growth factor II mRNA-binding protein. J Biol Chem. 2000;275:29562–9.

    Article  PubMed  CAS  Google Scholar 

  17. Zirkel A, Lederer M, Stohr N, Pazaitis N, Huttelmaier S. IGF2BP1 promotes mesenchymal cell properties and migration of tumor-derived cells by enhancing the expression of LEF1 and SNAI2 (SLUG). Nucleic Acids Res. 2013;41:6618–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Ghoshal A, Rodrigues LC, Gowda CP, Elcheva IA, Liu Z, Abraham T, et al. Extracellular vesicle-dependent effect of RNA-binding protein IGF2BP1 on melanoma metastasis. Oncogene. 2019;38:4182–96.

  19. Rosenfeld YB, Krumbein M, Yeffet A, Schiffmann N, Mishalian I, Pikarsky E, et al. VICKZ1 enhances tumor progression and metastasis in lung adenocarcinomas in mice. Oncogene. 2019;38:4169–81.

  20. Dimitriadis E, Trangas T, Milatos S, Foukas PG, Gioulbasanis I, Courtis N, et al. Expression of oncofetal RNA-binding protein CRD-BP/IMP1 predicts clinical outcome in colon cancer. Int J Cancer. 2007;121:486–94.

    Article  PubMed  CAS  Google Scholar 

  21. Kobel M, Weidensdorfer D, Reinke C, Lederer M, Schmitt WD, Zeng K, et al. Expression of the RNA-binding protein IMP1 correlates with poor prognosis in ovarian carcinoma. Oncogene. 2007;26:7584–9.

    Article  PubMed  CAS  Google Scholar 

  22. Bell JL, Turlapati R, Liu T, Schulte JH, Huttelmaier S. IGF2BP1 harbors prognostic significance by gene gain and diverse expression in neuroblastoma. J Clin Oncol. 2015;33:1285–93.

    Article  PubMed  CAS  Google Scholar 

  23. Stoskus M, Eidukaite A, Griskevicius L. Defining the significance of IGF2BP1 overexpression in t(12;21)(p13;q22)-positive leukemia REH cells. Leuk Res. 2016;47:16–21.

    Article  PubMed  CAS  Google Scholar 

  24. Stoskus M, Gineikiene E, Valceckiene V, Valatkaite B, Pileckyte R, Griskevicius L. Identification of characteristic IGF2BP expression patterns in distinct B-ALL entities. Blood Cells Mol Dis. 2011;46:321–6.

    Article  PubMed  CAS  Google Scholar 

  25. Stoskus M, Vaitkeviciene G, Eidukaite A, Griskevicius L. ETV6/RUNX1 transcript is a target of RNA-binding protein IGF2BP1 in t(12;21)(p13;q22)-positive acute lymphoblastic leukemia. Blood Cells Mol Dis. 2016;57:30–4.

    Article  PubMed  CAS  Google Scholar 

  26. Wang S, Chim B, Su Y, Khil P, Wong M, Wang X, et al. Enhancement of LIN28B-induced hematopoietic reprogramming by IGF2BP3. Genes Dev. 2019;33:1048–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. de Vasconcellos JF, Tumburu L, Byrnes C, Lee YT, Xu PC, Li M, et al. IGF2BP1 overexpression causes fetal-like hemoglobin expression patterns in cultured human adult erythroblasts. Proc Natl Acad Sci USA. 2017;114:E5664–72.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Liao B, Patel M, Hu Y, Charles S, Herrick DJ, Brewer G. Targeted knockdown of the RNA-binding protein CRD-BP promotes cell proliferation via an insulin-like growth factor II-dependent pathway in human K562 leukemia cells. J Biol Chem. 2004;279:48716–24.

    Article  PubMed  CAS  Google Scholar 

  29. Abramovich C, Pineault N, Ohta H, Humphries RK. Hox genes: from leukemia to hematopoietic stem cell expansion. Ann NY Acad Sci. 2005;1044:109–16.

    Article  PubMed  CAS  Google Scholar 

  30. Umeda S, Yamamoto K, Murayama T, Hidaka M, Kurata M, Ohshima T, et al. Prognostic significance of HOXB4 in de novo acute myeloid leukemia. Hematology. 2012;17:125–31.

    Article  PubMed  CAS  Google Scholar 

  31. Zhang XB, Beard BC, Trobridge GD, Wood BL, Sale GE, Sud R, et al. High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector. J Clin Investig. 2008;118:1502–10.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Wang H, Jia XH, Chen JR, Yi YJ, Wang JY, Li YJ, et al. HOXB4 knockdown reverses multidrug resistance of human myelogenous leukemia K562/ADM cells by downregulating P-gp, MRP1 and BCRP expression via PI3K/Akt signaling pathway. Int J Oncol. 2016;49:2529–37.

    Article  PubMed  CAS  Google Scholar 

  33. Kusakabe M, Sun AC, Tyshchenko K, Wong R, Nanda A, Shanna C, et al. Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia. Nat Commun. 2019;10:2913.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Pelicci PG, Lanfrancone L, Brathwaite MD, Wolman SR, Dalla-Favera R. Amplification of the c-myb oncogene in a case of human acute myelogenous leukemia. Science. 1984;224:1117–21.

    Article  PubMed  CAS  Google Scholar 

  35. Lahortiga I, De Keersmaecker K, Van Vlierberghe P, Graux C, Cauwelier B, Lambert F, et al. Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia. Nat Genet. 2007;39:593–5.

    Article  PubMed  CAS  Google Scholar 

  36. Clappier E, Cuccuini W, Kalota A, Crinquette A, Cayuela JM, Dik WA, et al. The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood. 2007;110:1251–61.

    Article  PubMed  CAS  Google Scholar 

  37. Somervaille TC, Matheny CJ, Spencer GJ, Iwasaki M, Rinn JL, Witten DM, et al. Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. Cell Stem Cell. 2009;4:129–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Zuber J, Rappaport AR, Luo W, Wang E, Chen C, Vaseva AV, et al. An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance. Genes Dev. 2011;25:1628–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Jackson B, Brocker C, Thompson DC, Black W, Vasiliou K, Nebert DW, et al. Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genomics. 2011;5:283–303.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Gasparetto M, Smith CA. ALDHs in normal and malignant hematopoietic cells: potential new avenues for treatment of AML and other blood cancers. Chem Biol Interact. 2017;276:46–51.

    Article  PubMed  CAS  Google Scholar 

  41. Flahaut M, Jauquier N, Chevalier N, Nardou K, Balmas Bourloud K, Joseph JM, et al. Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma. BMC Cancer. 2016;16:781.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Lohberger B, Rinner B, Stuendl N, Absenger M, Liegl-Atzwanger B, Walzer SM, et al. Aldehyde dehydrogenase 1, a potential marker for cancer stem cells in human sarcoma. PLoS ONE. 2012;7:e43664.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Muzio G, Maggiora M, Paiuzzi E, Oraldi M, Canuto RA. Aldehyde dehydrogenases and cell proliferation. Free Radic Biol Med. 2012;52:735–46.

    Article  PubMed  CAS  Google Scholar 

  44. Vassalli G. Aldehyde dehydrogenases: not just markers, but functional regulators of stem cells. Stem Cells Int. 2019;2019:3904645.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20:285–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This study was supported by the NIH grant R01 AR063361 (VSS), NIH Intramural Research Program of the NIAID (SAM), and NIAMS (MH). The authors thankful to Drs Chunhua Song and Joel Yisraeli for the gift of reagents. We also thankful to Yuka Imamura and Penn State Cancer Institute Genomics Sciences, Joe Bednarczyk and Flow Cytometry Core for help with data acquisition and analysis. We thank Gustavo Gutierrez-Cruz and Stefania Dell’Orso (NIAMS) for sequencing the PAR-CLIP libraries, and NIAID Office of Cyber Infrastructure and Computational Biology for high-performance computing.

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Authors and Affiliations

  1. Division of Pediatric Hematology and Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA

    Irina A. Elcheva, Tyler Wood, Kathryn Chiarolanzio, Vikash Singh, Chethana P. Gowda, Qingli Lu, Sinisa Dovat, Zhenqiu Liu & Vladimir S. Spiegelman

  2. Integrative Immunobiology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Bryan Chim, Madeline Wong & Stefan A. Muljo

  3. Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Markus Hafner

  4. Department of Public Health Sciences, Pennsylvania State University College of Medicine, Penn State Cancer Institute, Hershey, PA, USA

    Zhenqiu Liu

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  1. Irina A. Elcheva
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Elcheva, I.A., Wood, T., Chiarolanzio, K. et al. RNA-binding protein IGF2BP1 maintains leukemia stem cell properties by regulating HOXB4, MYB, and ALDH1A1. Leukemia 34, 1354–1363 (2020). https://doi.org/10.1038/s41375-019-0656-9

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