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.
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Dreyfuss G, Matunis MJ, Piñol-Roma S, Burd CG. hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem. 1993;62:289–321.
Geuens T, Bouhy D, Timmerman V. The hnRNP family: insights into their role in health and disease. Hum Genet. 2016;135:851–67.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Sherbenou DW, Druker BJ. Applying the discovery of the Philadelphia chromosome. J Clin Investig. 2007;117:2067–74.
Sloma I, Jiang X, Eaves AC, Eaves CJ. Insights into the stem cells of chronic myeloid leukemia. Leukemia. 2010;24:1823–33.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Perrotti D, Neviani P. From mRNA metabolism to cancer therapy: chronic myelogenous leukemia shows the way. Clin Cancer Res. 2007;13:1638–42.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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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