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Transcriptional control and signal transduction, cell cycle

BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4

Leukemia volume 29, pages 2248–2256 (2015)Cite this article

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Abstract

Although high brain and acute leukemia, cytoplasmic (BAALC) expression is a well-characterized poor prognostic factor in acute myeloid leukemia (AML), neither the exact mechanisms by which BAALC drives leukemogenesis and drug resistance nor therapeutic approaches against BAALC-high AML have been properly elucidated. In this study, we found that BAALC induced cell-cycle progression of leukemia cells by sustaining extracellular signal-regulated kinase (ERK) activity through an interaction with a scaffold protein MEK kinase-1 (MEKK1), which inhibits the interaction between ERK and MAP kinase phosphatase 3 (MKP3/DUSP6). BAALC conferred chemoresistance in AML cells by upregulating ATP-binding cassette proteins in an ERK-dependent manner, which can be therapeutically targeted by MEK inhibitor. We also demonstrated that BAALC blocks ERK-mediated monocytic differentiation of AML cells by trapping Krüppel-like factor 4 (KLF4) in the cytoplasm and inhibiting its function in the nucleus. Consequently, MEK inhibition therapy synergizes with KLF4 induction and is highly effective against BAALC-high AML cells both in vitro and in vivo. Our data provide a molecular basis for the role of BAALC in regulating proliferation and differentiation of AML cells and highlight the unique dual function of BAALC as an attractive therapeutic target against BAALC-high AML.

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References

  1. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453–474.

    Article  PubMed  Google Scholar 

  2. Langer C, Radmacher MD, Ruppert AS, Whitman SP, Paschka P, Mrózek K et al. High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study. Blood 2008; 111: 5371–5379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Baldus CD, Tanner SM, Ruppert AS, Whitman SP, Archer KJ, Marcucci G et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood 2003; 102: 1613–1618.

    Article  CAS  PubMed  Google Scholar 

  4. Damiani D, Tiribelli M, Franzoni A, Michelutti A, Fabbro D, Cavallin M et al. BAALC overexpression retains its negative prognostic role across all cytogenetic risk groups in acute myeloid leukemia patients. Am J Hematol 2013; 88: 848–852.

    Article  CAS  PubMed  Google Scholar 

  5. Tanner SM, Austin JL, Leone G, Rush LJ, Plass C, Heinonen K et al. BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. Proc Natl Acad Sci USA 2001; 98: 13901–13906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Baldus CD, Tanner SM, Kusewitt DF, Liyanarachchi S, Choi C, Caligiuri MA et al. BAALC, a novel marker of human hematopoietic progenitor cells. Exp Hematol 2003; 31: 1051–1056.

    CAS  PubMed  Google Scholar 

  7. Blume-Jensen P, Hunter T . Oncogenic kinase signalling. Nature 2001; 411: 355–365.

    Article  CAS  PubMed  Google Scholar 

  8. Towatari M, Iida H, Tanimoto M, Iwata H, Hamaguchi M, Saito H . Constitutive activation of mitogen-activated protein kinase pathway in acute leukemia cells. Leukemia 1997; 11: 479–484.

    Article  CAS  PubMed  Google Scholar 

  9. Jain N, Curran E, Iyengar NM, Diaz-Flores E, Kunnavakkam R, Popplewell L et al. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res 2014; 20: 490–498.

    Article  CAS  PubMed  Google Scholar 

  10. Karandikar M, Xu S, Cobb MH . MEKK1 binds raf-1 and the ERK2 cascade components. J Biol Chem 2000; 275: 40120–40127.

    Article  CAS  PubMed  Google Scholar 

  11. Jin JO, Song MG, Kim YN, Park JI, Kwak JY . The mechanism of fucoidan-induced apoptosis in leukemic cells: involvement of ERK1/2, JNK, glutathione, and nitric oxide. Mol Carcinog 2010; 49: 771–782.

    CAS  PubMed  Google Scholar 

  12. Nakamura Y, Yujiri T, Nawata R, Tagami K, Tanizawa Y . MEK kinase 1 is essential for Bcr-Abl-induced STAT3 and self-renewal activity in embryonic stem cells. Oncogene 2005; 24: 7592–7598.

    Article  CAS  PubMed  Google Scholar 

  13. Santos SD, Verveer PJ, Bastiaens PI . Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nat Cell Biol 2007; 9: 324–330.

    Article  CAS  PubMed  Google Scholar 

  14. Deschênes-Simard X, Gaumont-Leclerc MF, Bourdeau V, Lessard F, Moiseeva O, Forest V et al. Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation. Genes Dev 2013; 27: 900–915.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chen ZY, Tseng CC . 15-deoxy-Delta12,14 prostaglandin J2 up-regulates Kruppel-like factor 4 expression independently of peroxisome proliferator-activated receptor gamma by activating the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signal transduction pathway in HT-29 colon cancer cells. Mol Pharmacol 2005; 68: 1203–1213.

    Article  CAS  PubMed  Google Scholar 

  16. Feinberg MW, Wara AK, Cao Z, Lebedeva MA, Rosenbauer F, Iwasaki H et al. The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation. EMBO J 2007; 26: 4138–4148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yoshimi A, Goyama S, Watanabe-Okochi N, Yoshiki Y, Nannya Y, Nitta E et al. Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins. Blood 2011; 117: 3617–3628.

    Article  CAS  PubMed  Google Scholar 

  18. Kim MO, Kim SH, Cho YY, Nadas J, Jeong CH, Yao K et al. ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4. Nat Struct Mol Biol 2012; 19: 283–290.

    Article  CAS  PubMed  Google Scholar 

  19. Kim Y, Rice AE, Denu JM . Intramolecular dephosphorylation of ERK by MKP3. Biochemistry 2003; 42: 15197–15207.

    Article  CAS  PubMed  Google Scholar 

  20. Santamaria C, Chillon MC, Garcia-Sanz R, Perez C, Caballero MD, Mateos MV et al. BAALC is an important predictor of refractoriness to chemotherapy and poor survival in intermediate-risk acute myeloid leukemia (AML). Ann Hematol 2010; 89: 453–458.

    Article  CAS  PubMed  Google Scholar 

  21. Abrams SL, Steelman LS, Shelton JG, Wong EW, Chappell WH, Bäsecke J et al. The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle 2010; 9: 1781–1791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chang G . Multidrug resistance ABC transporters. FEBS Lett 2003; 555: 102–105.

    Article  CAS  PubMed  Google Scholar 

  23. Shen H, Xu W, Luo W, Zhou L, Yong W, Chen F et al. Upregulation of mdr1 gene is related to activation of the MAPK/ERK signal transduction pathway and YB-1 nuclear translocation in B-cell lymphoma. Exp Hematol 2011; 39: 558–569.

    Article  CAS  PubMed  Google Scholar 

  24. El Azreq MA, Naci D, Aoudjit F . Collagen/β1 integrin signaling up-regulates the ABCC1/MRP-1 transporter in an ERK/MAPK-dependent manner. Mol Biol Cell 2012; 23: 3473–3484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Imai Y, Ohmori K, Yasuda S, Wada M, Suzuki T, Fukuda K et al. Breast cancer resistance protein/ABCG2 is differentially regulated downstream of extracellular signal-regulated kinase. Cancer Sci 2009; 100: 1118–1127.

    Article  CAS  PubMed  Google Scholar 

  26. Lai JK, Wu HC, Shen YC, Hsieh HY, Yang SY, Chang CC . Krüppel-like factor 4 is involved in cell scattering induced by hepatocyte growth factor. J Cell Sci 2012; 125: 4853–4864.

    Article  CAS  PubMed  Google Scholar 

  27. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL . Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 2011; 11: 558–572.

    Article  CAS  PubMed  Google Scholar 

  28. Rowland BD . Peeper DS. KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer 2006; 6: 11–23.

    Article  CAS  PubMed  Google Scholar 

  29. Miranda MB, McGuire TF, Johnson DE . Importance of MEK-1/-2 signaling in monocytic and granulocytic differentiation of myeloid cell lines. Leukemia 2002; 16: 683–692.

    Article  CAS  PubMed  Google Scholar 

  30. Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D . MEK and the inhibitors: from bench to bedside. J Hematol Oncol 2013; 6: 27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cho SD, Chintharlapalli S, Abdelrahim M, Papineni S, Liu S, Guo J et al. 5,5'-Dibromo-bis(3'-indolyl)methane induces Kruppel-like factor 4 and p21 in colon cancer cells. Mol Cancer Ther 2008; 7: 2109–2120.

    Article  CAS  PubMed  Google Scholar 

  32. Eisfeld AK, Marcucci G, Maharry K, Schwind S, Radmacher MD, Nicolet D et al. miR-3151 interplays with its host gene BAALC and independently affects outcome of patients with cytogenetically normal acute myeloid leukemia. Blood 2012; 120: 249–258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Eisfeld AK, Schwind S, Patel R, Huang X, Santhanam R, Walker CJ et al. Intronic miR-3151 within BAALC drives leukemogenesis by deregulating the TP53 pathway. Sci Signal 2014; 7: ra36.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Eisfeld AK, Marcucci G, Liyanarachchi S, Döhner K, Schwind S, Maharry K et al. Heritable polymorphism predisposes to high BAALC expression in acute myeloid leukemia. Proc Natl Acad Sci USA 2012; 109: 6668–6673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Heuser M, Berg T, Kuchenbauer F, Lai CK, Park G, Fung S et al. Functional role of BAALC in leukemogenesis. Leukemia 2012; 26: 532–536.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr T Kitamura for platinum-A (Plat-A) packaging cells, Dr H Miyoshi for lentiviral vectors of CSII-EF-MCS-IRES2-Venus, CSII-EF-MCS-IRES2-hKO1, pENTR4-H1tetOx1, CSIV-TRE-RfA-EF-KT, psPAX2 and pMD2.G, Dr E Takekawa for CA-MEK1 and MEKK1, Dr T Furukawa for MKP3, Dr S Yamanaka for KLF4, Dr M Ogata for ERK1 and Dr A de la Chapelle for BAALC.

Author Contributions

KM designed research, performed experiments, analyzed data and wrote the manuscript. YM designed and supervised research, and wrote the manuscript. KK designed research. HY and SM supervised two-hybrid screening. JK, YK and TS commented on the research direction and wrote the manuscript. MK initiated the study, supervised research direction and wrote the manuscript.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    K Morita, Y Masamoto, K Kataoka, J Koya, Y Kagoya, T Sato & M Kurokawa

  2. Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

    H Yashiroda & S Murata

  3. Department of Transfusion Medicine, The University of Tokyo Hospital, Tokyo, Japan

    T Sato

  4. Department of Cell Therapy and Transplantation, The University of Tokyo Hospital, Tokyo, Japan

    M Kurokawa

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  1. K Morita
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Correspondence to M Kurokawa.

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Morita, K., Masamoto, Y., Kataoka, K. et al. BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. Leukemia 29, 2248–2256 (2015). https://doi.org/10.1038/leu.2015.137

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