Stem cell biology

Targeting RNA-binding proteins in acute and chronic leukemia

Abstract

RNA-binding proteins (RBPs) play a crucial role in cellular physiology by regulating RNA processing, translation, and turnover. In neoplasms, RBP support of cancer-relevant expression of alternatively spliced, modified, and stabilized mRNA transcripts is essential to self-renewal, proliferation, and adaptation to stress. In this review, we assess the impact of key families of RBPs in leukemogenesis, review progress in targeting those proteins with small molecules, and discuss how multilevel composition of posttranscriptional regulation of gene expression could be used for potential therapies in acute and chronic 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: RNA-binding proteins involved in leukemogenesis.

References

  1. 1.

    Hentze MW, Castello A, Schwarzl T, Preiss T. A brave new world of RNA-binding proteins. Nat Rev Mol Cell Biol. 2018;19:327–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Nishikura K. A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol. 2016;17:83–96.

    CAS  PubMed  Google Scholar 

  3. 3.

    Lamers MM, van den Hoogen BG, Haagmans BL ADAR1: “Editor-in-Chief” of cytoplasmic innate immunity. Front Immunol 2019;10:1763.

  4. 4.

    Wang Q, Khillan J, Gadue P, Nishikura K. Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science. 2000;290:1765–8.

    CAS  PubMed  Google Scholar 

  5. 5.

    Liddicoat BJ, Piskol R, Chalk AM, Ramaswami G, Higuchi M, Hartner JC, et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science. 2015;349:1115–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    XuFeng R, Boyer MJ, Shen H, Li Y, Yu H, Gao Y, et al. ADAR1 is required for hematopoietic progenitor cell survival via RNA editing. Proc Natl Acad Sci USA. 2009;106:17763–8.

    PubMed  Google Scholar 

  7. 7.

    Ma CH, Chong JH, Guo Y, Zeng HM, Liu SY, Xu LL, et al. Abnormal expression of ADAR1 isoforms in Chinese pediatric acute leukemias. Biochem Biophys Res Commun. 2011;406:245–51.

    CAS  PubMed  Google Scholar 

  8. 8.

    Xiao H, Cheng Q, Wu X, Tang Y, Liu J, Li X. ADAR1 may be involved in the proliferation of acute myeloid leukemia cells via regulation of the Wnt pathway. Cancer Manag Res. 2019;11:8547–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Jiang Q, Crews LA, Barrett CL, Chun H-J, Court AC, Isquith JM, et al. ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. Proc Natl Acad Sci USA. 2013;110:1041–6.

    CAS  PubMed  Google Scholar 

  10. 10.

    Zipeto MA, Court AC, Sadarangani A, Delos Santos NP, Balaian L, Chun HJ, et al. ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis. Cell Stem Cell. 2016;19:177–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Crews LA, Jiang Q, Zipeto MA, Lazzari E, Court AC, Ali S, et al. An RNA editing fingerprint of cancer stem cell reprogramming. J Transl Med. 2015;13:52.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Jiang Q, Isquith J, Zipeto MA, Diep RH, Pham J, Delos Santos N, et al. Hyper-editing of cell-cycle regulatory and tumor suppressor RNA promotes malignant progenitor propagation. Cancer Cell. 2019;35:81–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Gannon HS, Zou T, Kiessling MK, Gao GF, Cai D, Choi PS, et al. Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells. Nat Commun. 2018;9:5450.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ishizuka JJ, Manguso RT, Cheruiyot CK, Bi K, Panda A, Iracheta-Vellve A, et al. Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature. 2019;565:43–48.

    CAS  PubMed  Google Scholar 

  15. 15.

    Vu LP, Cheng Y, Kharas MG. The Biology of m(6)A RNA methylation in normal and malignant hematopoiesis. Cancer Disco. 2019;9:25–33.

    CAS  Google Scholar 

  16. 16.

    Shi H, Wei J, He C. Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell. 2019;74:640–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Martinez NM, Gilbert WV. Pre-mRNA modifications and their role in nuclear processing. Quant Biol. 2018;6:210–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Han SH, Choe J. Diverse molecular functions of m(6)A mRNA modification in cancer. Exp Mol Med. 2020;52:738–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millan-Zambrano G, Robson SC, et al. Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control. Nature. 2017;552:126–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Vu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, et al. The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 2017;23:1369–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Weng H, Huang H, Wu H, Qin X, Zhao BS, Dong L, et al. METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m(6)A Modification. Cell Stem Cell. 2018;22:191–205.

    CAS  PubMed  Google Scholar 

  22. 22.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Sorci M, Ianniello Z, Cruciani S, Larivera S, Ginistrelli LC, Capuano E, et al. METTL3 regulates WTAP protein homeostasis. Cell Death Dis. 2018;9:796.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014;24:177–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Bansal H, Yihua Q, Iyer SP, Ganapathy S, Proia DA, Penalva LO, et al. WTAP is a novel oncogenic protein in acute myeloid leukemia. Leukemia. 2014;28:1171–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M, et al. m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 2016;537:369–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Zhang L, Tran N-T, Su H, Wang R, Lu Y, Tang H, et al. Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing. Elife. 2015;4:e07938.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, et al. FTO plays an oncogenic role in acute myeloid leukemia as a N(6)-methyladenosine RNA demethylase. Cancer Cell. 2017;31:127–41.

    PubMed  Google Scholar 

  29. 29.

    Su R, Dong L, Li Y, Gao M, Han L, Wunderlich M, et al. Targeting FTO suppresses cancer stem cell maintenance and immune evasion. Cancer Cell. 2020;38:79–96.

    CAS  PubMed  Google Scholar 

  30. 30.

    Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H, et al. Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia. Cancer Cell. 2019;35:677–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Mauer J, Sindelar M, Despic V, Guez T, Hawley BR, Vasseur JJ, et al. FTO controls reversible m(6)Am RNA methylation during snRNA biogenesis. Nat Chem Biol. 2019;15:340–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Shen C, Sheng Y, Zhu AC, Robinson S, Jiang X, Dong L, et al. RNA demethylase ALKBH5 selectively promotes tumorigenesis and cancer stem cell self-renewal in acute myeloid leukemia. Cell Stem Cell. 2020;27:64–80.

    CAS  PubMed  Google Scholar 

  33. 33.

    Wang J, Li Y, Wang P, Han G, Zhang T, Chang J, et al. Leukemogenic chromatin alterations promote AML leukemia stem cells via a KDM4C-ALKBH5-AXL signaling axis. Cell Stem Cell. 2020;27:81–97.

    CAS  PubMed  Google Scholar 

  34. 34.

    Paris J, Morgan M, Campos J, Spencer GJ, Shmakova A, Ivanova I, et al. Targeting the RNA m(6)A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia. Cell Stem Cell. 2019;25:137–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Cully M. Chemical inhibitors make their RNA epigenetic mark. Nat Rev Drug Disco. 2019;18:892–4.

    CAS  Google Scholar 

  36. 36.

    El Marabti E, Younis I. The cancer spliceome: reprograming of alternative splicing in cancer. Front Mol Biosci. 2018;5(Sep):80–80.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Obeng EA, Stewart C, Abdel-Wahab O. Altered RNA processing in cancer pathogenesis and therapy. Cancer Disco. 2019;9:1493–510.

    CAS  Google Scholar 

  38. 38.

    Adamia S, Haibe-Kains B, Pilarski PM, Bar-Natan M, Pevzner S, Avet-Loiseau H, et al. A genome-wide aberrant RNA splicing in patients with acute myeloid leukemia identifies novel potential disease markers and therapeutic targets. Clin Cancer Res. 2014;20:1135–45.

    CAS  PubMed  Google Scholar 

  39. 39.

    Park S, Supek F, Lehner B. Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits. Nat Commun. 2018;9:2601.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Jung H, Lee D, Lee J, Park D, Kim YJ, Park WY, et al. Intron retention is a widespread mechanism of tumor-suppressor inactivation. Nat Genet. 2015;47:1242–8.

    CAS  PubMed  Google Scholar 

  41. 41.

    Abrahamsson AE, Geron I, Gotlib J, Dao K-HT, Barroga CF, Newton IG, et al. Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci. 2009;106:3925–9.

    CAS  PubMed  Google Scholar 

  42. 42.

    Puente XS, Beà S, Valdés-Mas R, Villamor N, Gutiérrez-Abril J, Martín-Subero JI, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015;526:519–24.

    CAS  PubMed  Google Scholar 

  43. 43.

    Asnani M, Hayer KE, Naqvi AS, Zheng S, Yang SY, Oldridge D, et al. Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19. Leukemia. 2020;34:1202–7.

    PubMed  Google Scholar 

  44. 44.

    Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–69.

    CAS  PubMed  Google Scholar 

  45. 45.

    Taylor J, Lee SC. Mutations in spliceosome genes and therapeutic opportunities in myeloid malignancies. Genes Chromosomes Cancer. 2019;58:889–902.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Cretu C, Schmitzova J, Ponce-Salvatierra A, Dybkov O, De Laurentiis EI, Sharma K, et al. Molecular architecture of SF3b and structural consequences of its cancer-related mutations. Mol Cell. 2016;64:307–19.

    CAS  PubMed  Google Scholar 

  47. 47.

    Wang L, Brooks AN, Fan J, Wan Y, Gambe R, Li S, et al. Transcriptomic characterization of SF3B1 mutation reveals its pleiotropic effects in chronic lymphocytic leukemia. Cancer Cell. 2016;30:750–63.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Kim E, Ilagan JO, Liang Y, Daubner GM, Lee SC, Ramakrishnan A, et al. SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell. 2015;27:617–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Black KL, Naqvi AS, Asnani M, Hayer KE, Yang SY, Gillespie E, et al. Aberrant splicing in B-cell acute lymphoblastic leukemia. Nucleic Acids Res. 2018;46:11357–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Wang E, Lu SX, Pastore A, Chen X, Imig J, Chun-Wei Lee S, et al. Targeting an RNA-binding protein network in acute myeloid leukemia. Cancer Cell. 2019;35:369–84.

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Yamauchi T, Masuda T, Canver MC, Seiler M, Semba Y, Shboul M, et al. Genome-wide CRISPR-Cas9 screen identifies leukemia-specific dependence on a Pre-mRNA metabolic pathway regulated by DCPS. Cancer Cell. 2018;33:386–400.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Bajaj J, Hamilton M, Shima Y, Chambers K, Spinler K, Van Nostrand EL, et al. An in vivo genome-wide CRISPR screen identifies the RNA-binding protein Staufen2 as a key regulator of myeloid leukemia. Nat Cancer. 2020;1:410–22.

    Google Scholar 

  53. 53.

    Tian B, Manley JL. Alternative polyadenylation of mRNA precursors. Nat Rev Mol Cell Biol. 2017;18:18–30.

    CAS  Google Scholar 

  54. 54.

    Danckwardt S, Hentze MW, Kulozik AE. 3’ end mRNA processing: molecular mechanisms and implications for health and disease. EMBO J. 2008;27:482–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Shima T, Davis AG, Miyauchi S, Kochi Y, Johnson DT, Stoner SA, et al.CPSF1 regulates AML1-ETO fusion gene polyadenylation and stability in t(8;21) acute myelogenous leukemia. Blood. 2017;130:2498–2498.

    Google Scholar 

  56. 56.

    Ye C, Zhou Q, Hong Y, Li QQ. Role of alternative polyadenylation dynamics in acute myeloid leukaemia at single-cell resolution. RNA Biol. 2019;16:785–97.

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Venters CC, Oh JM, Di C, So BR, Dreyfuss G. U1 snRNP telescripting: suppression of premature transcription termination in introns as a new layer of gene regulation. Cold Spring Harb Perspect Biol. 2019;11:1–15.

    Google Scholar 

  58. 58.

    Shuai S, Suzuki H, Diaz-Navarro A, Nadeu F, Kumar SA, Gutierrez-Fernandez A, et al. The U1 spliceosomal RNA is recurrently mutated in multiple cancers. Nature. 2019;574:712–6.

    CAS  PubMed  Google Scholar 

  59. 59.

    Oh J-M, Venters CC, Di C, Pinto AM, Wan L, Younis I, et al. U1 snRNP regulates cancer cell migration and invasion in vitro. Nat Commun. 2020;11:1–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Baou M, Norton JD, Murphy JJ. AU-rich RNA binding proteins in hematopoiesis and leukemogenesis. Blood. 2011;118:5732–40.

    CAS  PubMed  Google Scholar 

  61. 61.

    Salton M, Misteli T. Small molecule modulators of Pre-mRNA splicing in cancer therapy. Trends Mol Med. 2016;22:28–37.

    CAS  PubMed  Google Scholar 

  62. 62.

    Seiler M, Yoshimi A, Darman R, Chan B, Keaney G, Thomas M, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018;24:497–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Han T, Goralski M, Gaskill N, Capota E, Kim J, Ting TC, et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science. 2017;356:3755.

    Google Scholar 

  64. 64.

    Fedoriw A, Rajapurkar SR, O’Brien S, Gerhart SV, Mitchell LH, Adams ND, et al. Anti-tumor activity of the type I PRMT inhibitor, GSK3368715, synergizes with PRMT5 inhibition through MTAP loss. Cancer Cell. 2019;36:100–14.

    CAS  PubMed  Google Scholar 

  65. 65.

    Fong JY, Pignata L, Goy PA, Kawabata KC, Lee SC, Koh CM, et al. Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation. Cancer Cell. 2019;36:194–209.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Kohler A, Hurt E. Exporting RNA from the nucleus to the cytoplasm. Nat Rev Mol Cell Biol. 2007;8:761–73.

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    Mahipal A, Malafa M. Importins and exportins as therapeutic targets in cancer. Pharm Ther. 2016;164:135–43.

    CAS  Google Scholar 

  68. 68.

    Talati C, Sweet KL. Nuclear transport inhibition in acute myeloid leukemia: recent advances and future perspectives. Int J Hematol Oncol. 2018;7:IJH04–IJH04.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Topisirovic I, Guzman ML, McConnell MJ, Licht JD, Culjkovic B, Neering SJ, et al. Aberrant eukaryotic translation initiation factor 4E-dependent mRNA transport impedes hematopoietic differentiation and contributes to leukemogenesis. Mol Cell Biol. 2003;23:8992–9002.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Culjkovic-Kraljacic B, Fernando TM, Marullo R, Calvo-Vidal N, Verma A, Yang S, et al. Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas. Blood. 2016;127:858–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Borden KL, Culjkovic-Kraljacic B. Ribavirin as an anti-cancer therapy: acute myeloid leukemia and beyond? Leuk Lymphoma. 2010;51:1805–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Zahreddine HA, Culjkovic-Kraljacic B, Assouline S, Gendron P, Romeo AA, Morris SJ, et al. The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature. 2014;511:90–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Rentas S, Holzapfel N, Belew MS, Pratt G, Voisin V, Wilhelm BT, et al. Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells. Nature. 2016;532:508–11.

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Nguyen DTT, Lu Y, Chu KL, Yang X, Park SM, Choo ZN, et al. HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells. Nat Commun. 2020;11:2026.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Park S-M, Gönen M, Vu L, Minuesa G, Tivnan P, Barlowe TS, et al. Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program. J Clin Invest. 2015;125:1286–98.

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Park SM, Cho H, Thornton AM, Barlowe TS, Chou T, Chhangawala S, et al. IKZF2 Drives Leukemia Stem Cell Self-Renewal and Inhibits Myeloid Differentiation. Cell Stem Cell. 2019;24:153–65.

    CAS  PubMed  Google Scholar 

  78. 78.

    Kwon HY, Bajaj J, Ito T, Blevins A, Konuma T, Weeks J, et al. Tetraspanin 3 is required for the development and propagation of acute myelogenous leukemia. Cell Stem Cell. 2015;17:152–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Ito T, Kwon HY, Zimdahl B, Congdon KL, Blum J, Lento WE, et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature. 2010;466:765–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Kharas MG, Lengner CJ, Al-Shahrour F, Bullinger L, Ball B, Zaidi S, et al. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med. 2010;16:903–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Hattori A, Tsunoda M, Konuma T, Kobayashi M, Nagy T, Glushka J, et al. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature. 2017;545:500–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Minuesa G, Albanese SK, Xie W, Kazansky Y, Worroll D, Chow A, et al. Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia. Nat Commun. 2019;10:2691.

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S, et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet. 2009;41:843–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Jiang X, Huang H, Li Z, Li Y, Wang X, Gurbuxani S, et al. Blockade of miR-150 maturation by MLL-fusion/MYC/LIN-28 is required for MLL-associated leukemia. Cancer Cell. 2012;22:524–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Chaudhuri AA, So AY, Mehta A, Minisandram A, Sinha N, Jonsson VD, et al. Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A. Proc Natl Acad Sci USA. 2012;109:4233–8.

    CAS  PubMed  Google Scholar 

  87. 87.

    Ransey E, Björkbom A, Lelyveld VS, Biecek P, Pantano L, Szostak JW, et al. Comparative analysis of LIN28-RNA binding sites identified at single nucleotide resolution. RNA Biol. 2017;14:1756–65.

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Yamashita S, Nagaike T, Tomita K. Crystal structure of the Lin28-interacting module of human terminal uridylyltransferase that regulates let-7 expression. Nat Commun. 2019;10:1960.

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Roos M, Pradere U, Ngondo RP, Behera A, Allegrini S, Civenni G, et al. A Small-Molecule Inhibitor of Lin28. ACS Chem Biol. 2016;11:2773–81.

    CAS  PubMed  Google Scholar 

  90. 90.

    Yu C, Wang L, Rowe RG, Han A, Ji W, McMahon C, et al. A nanobody targeting the LIN28:let-7 interaction fragment of TUT4 blocks uridylation of let-7. Proc Natl Acad Sci USA. 2020;117:4653–63.

    CAS  PubMed  Google Scholar 

  91. 91.

    Wang L, Rowe RG, Jaimes A, Yu C, Nam Y, Pearson DS, et al. Small-Molecule Inhibitors Disrupt let-7 Oligouridylation and Release the Selective Blockade of let-7 Processing by LIN28. Cell Rep. 2018;23:3091–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    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.

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    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;57:30–34.

    CAS  PubMed  Google Scholar 

  95. 95.

    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 Invest. 2016;126:1495–511.

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Busch B, Bley N, Müller S, Glaß M, Misiak D, Lederer M, et al. The oncogenic triangle of HMGA2, LIN28B and IGF2BP1 antagonizes tumor-suppressive actions of the let-7 family. Nucleic Acids Res. 2016;44:3845–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

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

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    He X, Li W, Liang X, Zhu X, Zhang L, Huang Y, et al. IGF2BP2 overexpression indicates poor survival in patients with acute myelocytic leukemia. Cell Physiol Biochem. 2018;51:1945–56.

    CAS  PubMed  Google Scholar 

  99. 99.

    Elcheva IA, Wood T, Chiarolanzio K, Chim B, Wong M, Singh V, et al. RNA-binding protein IGF2BP1 maintains leukemia stem cell properties by regulating HOXB4, MYB, and ALDH1A1. Leukemia. 2020;34:1354–63.

    CAS  PubMed  Google Scholar 

  100. 100.

    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.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported in part by the NIH NCI grants CA191550 and CA243167 (V.S.S.). The authors would like to thank Alexander Elchev and Rachael Mills for editorial help with the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Irina A. Elcheva.

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Elcheva, I.A., Spiegelman, V.S. Targeting RNA-binding proteins in acute and chronic leukemia. Leukemia (2020). https://doi.org/10.1038/s41375-020-01066-4

Download citation

Search