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.

  • Article
  • Published:

Oncogenic heterogeneous nuclear ribonucleoprotein D-like modulates the growth and imatinib response of human chronic myeloid leukemia CD34+ cells via pre-B-cell leukemia homeobox 1

Oncogene volume 39, pages 443–453 (2020)Cite this article

Subjects

Abstract

Chronic myeloid leukemia (CML) originates from normal hematopoietic stem cells acquiring BCR-ABL fusion gene, specific BCR-ABL inhibitors (e.g., imatinib mesylate, IM) have greatly improved patient management. However, some patients are still suffering from relapse and drug resistance, which urges better understanding of the growth/survival mechanisms of CML stem/progenitor cells. In the present study, the role and its underlying mechanism of heterogeneous nuclear ribonucleoprotein D-like (HNRPDL) in CML cells were investigated. Firstly, overexpression of HNRPDL promoted the growth of murine BaF3 cells in vitro and induced leukemia in vivo, which was enhanced by co-expression of BCR-ABL. Conversely, HNRPDL silencing inhibited colony-forming cell (CFC) production of CML CD34+ cells and attenuated BCR-ABL induced leukemia. In addition, HNRPDL modulated imatinib response of K562 cells and HNRPDL silencing sensitized CML CD34+ cells to imatinib treatment. Mechanistically, we found the stability of pre-B-cell leukemia homeobox 1 (PBX1) mRNA was sustained by HNRPDL through its binding to a specific motif (ACUAGC) in 3′-untranslated region (3′-UTR) of PBX1. The expression of PBX1 was significantly higher in CML CD34+ cells than that in control cells and PBX silencing inhibited the growth of CML cells and sensitized them to imatinib treatment. In contrast, overexpression of PBX1 elevated the CFC production of normal hematopoietic CD34+ cells and “rescued” HNRPDL silencing induced growth inhibition and imatinib sensitization. Taken together, our data have demonstrated that HNRPDL transforms hematopoietic cells and a novel HNRPDL/PBX1 axis plays an important role in human CML CD34+ cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Dreyfuss G, Matunis MJ, Piñol-Roma S, Burd CG. hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem. 1993;62:289–321.

    CAS  PubMed  Google Scholar 

  2. Geuens T, Bouhy D, Timmerman V. The hnRNP family: insights into their role in health and disease. Hum Genet. 2016;135:851–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang Y, Xiao X, Zhang J, Choudhury R, Robertson A, Li K, et al. A complex network of factors with overlapping affinities represses splicing through intronic elements. Nat Struct Mol Biol. 2013;20:36–45.

    PubMed  Google Scholar 

  4. Doi A, Shiosaka T, Takaoka Y, Yanagisawa K, Fujita S. Molecular cloning of the cDNA encoding A+ U-rich element RNA binding factor. Biochim Biophys Acta. 1998;1396:51–6.

    CAS  PubMed  Google Scholar 

  5. Tsuchiya N, Kamei D, Takano A, Matsui T, Yamada M. Cloning and characterization of a cDNA encoding a novel heterogeneous nuclear ribonucleoprotein-like protein and its expression in myeloid leukemia cells. J Biochem. 1998;123:499–507.

    CAS  PubMed  Google Scholar 

  6. Kawamura H, Tomozoe Y, Akagi T, Kamei D, Ochiai M, Yamada M. Identification of the nucleocytoplasmic shuttling sequence of heterogeneous nuclear ribonucleoprotein D-like protein JKTBP and its interaction with mRNA. J Biol Chem. 2002;277:2732–9.

    CAS  PubMed  Google Scholar 

  7. Imasaki T, Shimizu T, Hashimoto H, Hidaka Y, Kose S, Imamoto N, et al. Structural basis for substrate recognition and dissociation by human transportin 1. Mol Cell. 2007;28:57–67.

    CAS  PubMed  Google Scholar 

  8. Kamei D, Yamada M. Interactions of heterogeneous nuclear ribonucleoprotein D-like protein JKTBP and its domains with high-affinity binding sites. Gene. 2002;298:49–57.

    CAS  PubMed  Google Scholar 

  9. Bandiera A, Tell G, Marsich E, Scaloni A, Pocsfalvi G, Akintunde Akindahunsi A, et al. Cytosine-block telomeric type DNA-binding activity of hnRNP proteins from human cell lines. Arch Biochem Biophys. 2003;409:305–14.

    CAS  PubMed  Google Scholar 

  10. Reboll MR, Oumard A, Gazdag AC, Renger I, Ritter B, Schwarzer M, et al. NRF IRES activity is mediated by RNA binding protein JKTBP1 and a 14-nt RNA element. RNA. 2007;13:1328–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Omnus DJ, Mehrtens S, Ritter B, Resch K, Yamada M, Frank R, et al. JKTBP1 is involved in stabilization and IRES-dependent translation of NRF mRNAs by binding to 5′ and 3′ untranslated regions. J Mol Biol. 2011;407:492–504.

    CAS  PubMed  Google Scholar 

  12. Boopathi E, Lenka N, Prabu SK, Fang JK, Wilkinson F, Atchison M, et al. Regulation of murine cytochrome c oxidase Vb gene expression during myogenesis: YY-1 and heterogeneous nuclear ribonucleoprotein D-like protein (JKTBP1) reciprocally regulate transcription activity by physical interaction with the BERF-1/ZBP-89 factor. J Biol Chem. 2004;279:35242–54.

    CAS  PubMed  Google Scholar 

  13. Vieira NM, Naslavsky MS, Licinio L, Kok F, Schlesinger D, Vainzof M, et al. A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G). Hum Mol Genet. 2014;23:4103–10.

    CAS  PubMed  Google Scholar 

  14. Bonnet C, Andrieux J, Béri-Dexheimer M, Leheup B, Boute O, Manouvrier S, et al. Microdeletion at chromosome 4q21 defines a new emerging syndrome with marked growth restriction, mental retardation and absent or severely delayed speech. J Med Genet. 2010;47:377–84.

    CAS  PubMed  Google Scholar 

  15. Hu X, Chen X, Wu B, Soler IM, Chen S, Shen Y. Further defining the critical genes for the 4q21 microdeletion disorder. Am J Med Genet A. 2017;173:120–5.

    CAS  PubMed  Google Scholar 

  16. Kurokawa Y, Matoba R, Takemasa I, Nakamori S, Tsujie M, Nagano H, et al. Molecular features of non-B, non-C hepatocellular carcinoma: a PCR-array gene expression profiling study. J Hepatol. 2003;39:1004–12.

    CAS  PubMed  Google Scholar 

  17. Wu YY, Li H, Lv XY, Wei Q, Li X, Liu XY, et al. Overexpression of JKTBP1 induces androgen-independent LNCaP cell proliferation through activation of epidermal growth factor-receptor (EGF-R). Cell Biochem Funct. 2008;26:467–77.

    CAS  PubMed  Google Scholar 

  18. de Wit M, Kant H, Piersma SR, Pham TV, Mongera S, van Berkel MP, et al. Colorectal cancer candidate biomarkers identified by tissue secretome proteome profiling. J Proteom. 2014;99:26–39.

    Google Scholar 

  19. Zhang P, Ji D, Hu X, Ni H, Ma W, Zhang X, et al. Oncogenic heterogeneous nuclear ribonucleoprotein D-like promotes the growth of human colon cancer SW620 cells via its regulation of cell-cycle. Acta Biochim Biophys Sin. 2018;50:880–7.

    CAS  PubMed  Google Scholar 

  20. Zhou H, Ge Y, Sun L, Ma W, Wu J, Zhang X, et al. Growth arrest specific 2 is up-regulated in chronic myeloid leukemia cells and required for their growth. PLoS ONE. 2014;9:e86195.

    PubMed  PubMed Central  Google Scholar 

  21. Al-Ghoul M, Brück TB, Lauer-Fields JL, Asirvatham VS, Zapata C, Kerr RG, et al. Comparative proteomic analysis of matched primary and metastatic melanoma cell lines. J Proteome Res. 2008;7:4107–18.

    CAS  PubMed  Google Scholar 

  22. van Erk MJ, Roepman P, van der Lende TR, Stierum RH, Aarts JM, van Bladeren PJ, et al. Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005;44:143–56.

    PubMed  Google Scholar 

  23. Peng X, Gong F, Xie G, Zhao Y, Tang M, Yu L, et al. A proteomic investigation into adriamycin chemo-resistance of human leukemia K562 cells. Mol Cell Biochem. 2011;351:233–41.

    CAS  PubMed  Google Scholar 

  24. Bertagnolo V, Grassilli S, Petretto A, Lambertini E, Astati L, Bruschi M, et al. Nuclear proteome analysis reveals a role of Vav1 in modulating RNA processing during maturation of tumoral promyelocytes. J Proteom. 2011;75:398–409.

    CAS  Google Scholar 

  25. Sherbenou DW, Druker BJ. Applying the discovery of the Philadelphia chromosome. J Clin Investig. 2007;117:2067–74.

    CAS  PubMed  Google Scholar 

  26. Sloma I, Jiang X, Eaves AC, Eaves CJ. Insights into the stem cells of chronic myeloid leukemia. Leukemia. 2010;24:1823–33.

    CAS  PubMed  Google Scholar 

  27. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Investig. 2011;121:396–409.

    CAS  PubMed  Google Scholar 

  28. Hamilton A, Helgason GV, Schemionek M, Zhang B, Myssina S, Allan EK, et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood. 2012;119:1501–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA. 2006;103:2794–9.

    CAS  PubMed  Google Scholar 

  30. Jiang X, Forrest D, Nicolini F, Turhan A, Guilhot J, Yip C, et al. Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate. Blood. 2010;116:2112–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Vegi NM, Klappacher J, Oswald F, Mulaw MA, Mandoli A, Thiel VN, et al. MEIS2 is an oncogenic partner in AML1-ETO-positive AML. Cell Rep. 2016;16:498–507.

    CAS  PubMed  Google Scholar 

  32. Lai CK, Norddahl GL, Maetzig T, Rosten P, Lohr T, Sanchez Milde L, et al. Meis2 as a critical player in MN1-induced leukemia. Blood. Cancer J. 2017;7:e613.

    CAS  Google Scholar 

  33. Shimabe M, Goyama S, Watanabe-Okochi N, Yoshimi A, Ichikawa M, Imai Y, et al. Pbx1 is a downstream target of Evi-1 in hematopoietic stem/progenitors and leukemic cells. Oncogene. 2009;28:4364–74.

    CAS  PubMed  Google Scholar 

  34. Xu X, Han K, Tang X, Zeng Y, Lin X, Zhao Y, et al. The ring finger protein RNF6 induces leukemia cell proliferation as a direct target of pre-B-cell leukemia homeobox 1. J Biol Chem. 2016;291:9617–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Guo X, Stratton L, Schrader JW. Expression of activated M-Ras in hemopoietic stem cells initiates leukemogenic transformation, immortalization and preferential generation of mast cells. Oncogene. 2006;25:4241–4.

    CAS  PubMed  Google Scholar 

  36. Perrotti D, Bonatti S, Trotta R, Martinez R, Skorski T, Salomoni P, et al. TLS/FUS, a pro-oncogene involved in multiple chromosomal translocations, is a novel regulator of BCR/ABL-mediated leukemogenesis. EMBO J. 1998;17:4442–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Trotta R, Vignudelli T, Candini O, Intine RV, Pecorari L, Guerzoni C, et al. BCR/ABL activates mdm2 mRNA translation via the La antigen. Cancer Cell. 2003;3:145–60.

    CAS  PubMed  Google Scholar 

  38. Perrotti D, Neviani P. From mRNA metabolism to cancer therapy: chronic myelogenous leukemia shows the way. Clin Cancer Res. 2007;13:1638–42.

    CAS  PubMed  Google Scholar 

  39. 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 

  40. Akindahunsi AA, Bandiera A, Manzini G. Vertebrate 2xRBD hnRNP proteins: a comparative analysis of genome, mRNA and protein sequences. Comput Biol Chem. 2005;29:13–23.

    CAS  PubMed  Google Scholar 

  41. Golan-Gerstl R, Cohen M, Shilo A, Suh SS, Bakàcs A, Coppola L, et al. Splicing factor hnRNP A2/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma. Cancer Res. 2011;71:4464–72.

    CAS  PubMed  Google Scholar 

  42. Deneault E, Cellot S, Faubert A, Laverdure JP, Fréchette M, Chagraoui J, et al. A functional screen to identify novel effectors of hematopoietic stem cell activity. Cell. 2009;137:369–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Hunger SP, Galili N, Carroll AJ, Crist WM, Link MP, Cleary ML. The t(1;19)(q23; p13) results in consistent fusion of E2A and PBX1 coding sequences in acute lymphoblastic leukemias. Blood. 1991;77:687–93.

    CAS  PubMed  Google Scholar 

  44. Kamps MP, Look AT, Baltimore D. The human t(1;19) translocation in pre-B ALL produces multiple nuclear E2A-Pbx1 fusion proteins with differing transforming potentials. Genes Dev. 1991;5:358–68.

    CAS  PubMed  Google Scholar 

  45. Dedera DA, Waller EK, LeBrun DP, Sen-Majumdar A, Stevens ME, Barsh GS, et al. Chimeric homeobox gene E2A-PBX1 induces proliferation, apoptosis, and malignant lymphomas in transgenic mice. Cell. 1993;74:833–43.

    CAS  PubMed  Google Scholar 

  46. Ficara F, Murphy MJ, Lin M, Cleary ML. Pbx1 regulates self-renewal of long-term hematopoietic stem cells by maintaining their quiescence. Cell Stem Cell. 2008;2:484–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhang X, Ma W, Cui J, Yao H, Zhou H, Ge Y, et al. Regulation of p21 by TWIST2 contributes to its tumor-suppressor function in human acute myeloid leukemia. Oncogene. 2015;34:3000–10.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China (Nos. 31771579, 31371392 to YZ, 81400113 to HZ, 81500119 to XZ, and 81800151 to WM), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Innovation Capability Development Project of Jiangsu Province (No. BM2015004).

Author information

Author notes

  1. These authors contributed equally: Dehuan Ji, Pengshan Zhang, Wenjuan Ma

  2. These authors are co-senior authors: Haixia Zhou, Yun Zhao

Authors and Affiliations

  1. Cyrus Tang Hematology Center, National Clinical Research Center for Hematologic Diseases, Soochow University, 215123, Suzhou, China

    Dehuan Ji, Pengshan Zhang, Wenjuan Ma, Yiwen Fei, Wen Xue, Yu Wang, Xiuyan Zhang & Yun Zhao

  2. The First Affiliated Hospital of Soochow University, National Clinical Research Center for Hematologic Diseases, 215006, Suzhou, China

    Haixia Zhou

  3. Collaborative Innovation Center of Hematology, Soochow University, 215006, Suzhou, China

    Yun Zhao

Authors
  1. Dehuan Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pengshan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenjuan Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yiwen Fei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiuyan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Haixia Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yun Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DJ, PZ, and WM performed most experimental work and PZ initiated the experimental study. YF, WX, YW, and XZ provided critical technical supports. HZ and YZ conceived the project and designed the study. H.Z. also supervised the quality of the clinical samples. YZ, HZ, DJ, PZ, and WM wrote the manuscript. All authors have read and approved this manuscript.

Corresponding authors

Correspondence to Haixia Zhou or Yun Zhao.

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ji, D., Zhang, P., Ma, W. et al. Oncogenic heterogeneous nuclear ribonucleoprotein D-like modulates the growth and imatinib response of human chronic myeloid leukemia CD34+ cells via pre-B-cell leukemia homeobox 1. Oncogene 39, 443–453 (2020). https://doi.org/10.1038/s41388-019-0998-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0998-9

Search

Advanced search

Quick links