Skip to main content
SpringerLink
Log in

The role of RAS effectors in BCR/ABL induced chronic myelogenous leukemia

  • Research Article
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

Abstract

BCR/ABL is the causative agent of chronic myelogenous leukemia (CML). Through structure/function analysis, several protein motifs have been determined to be important for the development of leukemogenesis. Tyrosine177 of BCR is a Grb2 binding site required for BCR/ABL-induced CML in mice. In the current study, we use a mouse bone marrow transduction/transplantation system to demonstrate that addition of oncogenic NRAS (NRASG12D) to a vector containing a BCR/ABLY177F mutant “rescues” the CML phenotype rapidly and efficiently. To further narrow down the pathways downstream of RAS that are responsible for this rescue effect, we utilize well-characterized RAS effector loop mutants and determine that the RAL pathway is important for rapid induction of CML. Inhibition of this pathway by a dominant negative RAL is capable of delaying disease progression. Results from the present study support the notion of RAL inhibition as a potential therapy for BCR/ABL-induced CML.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973; 243(5405): 290–293

    Article  PubMed  CAS  Google Scholar 

  2. Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 1984; 36(1): 93–99

    Article  PubMed  CAS  Google Scholar 

  3. McWhirter JR, Galasso DL, Wang JY. A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol Cell Biol 1993; 13(12): 7587–7595

    PubMed  CAS  Google Scholar 

  4. Zhang X, Subrahmanyam R, Wong R, Gross AW, Ren R. The NH (2)-terminal coiled-coil domain and tyrosine 177 play important roles in induction of a myeloproliferative disease in mice by Bcr-Abl. Mol Cell Biol 2001; 21(3): 840–853

    Article  PubMed  CAS  Google Scholar 

  5. Cortez D, Kadlec L, Pendergast AM. Structural and signaling requirements for BCR-ABL-mediated transformation and inhibition of apoptosis. Mol Cell Biol 1995; 15(10): 5531–5541

    PubMed  CAS  Google Scholar 

  6. Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 1990; 247(4946): 1079–1082

    Article  PubMed  CAS  Google Scholar 

  7. He Y, Wertheim JA, Xu L, Miller JP, Karnell FG, Choi JK, Ren R, Pear WS. The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl. Blood 2002; 99(8): 2957–2968

    Article  PubMed  CAS  Google Scholar 

  8. Million RP, Harakawa N, Roumiantsev S, Varticovski L, Van Etten RA. A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase. Mol Cell Biol 2004; 24(11): 4685–4695

    Article  PubMed  CAS  Google Scholar 

  9. Sattler M, Mohi MG, Pride YB, Quinnan LR, Malouf NA, Podar K, Gesbert F, Iwasaki H, Li S, Van Etten RA, Gu H, Griffin JD, Neel BG. Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell 2002; 1(5): 479–492

    Article  PubMed  CAS  Google Scholar 

  10. Goga A, McLaughlin J, Afar DE, Saffran DC, Witte ON. Alternative signals to RAS for hematopoietic transformation by the BCR-ABL oncogene. Cell 1995; 82(6): 981–988

    Article  PubMed  CAS  Google Scholar 

  11. Million RP, Van Etten RA. The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase. Blood 2000; 96(2): 664–670

    PubMed  CAS  Google Scholar 

  12. Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ, Der CJ. Increasing complexity of Ras signaling. Oncogene 1998; 17(11 Reviews): 1395–1413

    Article  PubMed  CAS  Google Scholar 

  13. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood 2000; 96(10): 3343–3356

    PubMed  CAS  Google Scholar 

  14. White MA, Nicolette C, Minden A, Polverino A, Van Aelst L, Karin M, Wigler MH. Multiple Ras functions can contribute to mammalian cell transformation. Cell 1995; 80(4): 533–541

    Article  PubMed  CAS  Google Scholar 

  15. Campbell PM, Singh A, Williams FJ, Frantz K, Ulkü AS, Kelley GG, Der CJ. Genetic and pharmacologic dissection of Ras effector utilization in oncogenesis. Methods Enzymol 2006; 407: 195–217

    PubMed  CAS  Google Scholar 

  16. Leicht DT, Balan V, Kaplun A, Singh-Gupta V, Kaplun L, Dobson M, Tzivion G. Raf kinases: function, regulation and role in human cancer. Biochim Biophys Acta 2007; 1773(8): 1196–1212

    Article  PubMed  CAS  Google Scholar 

  17. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 2007; 26(22): 3291–3310

    Article  PubMed  CAS  Google Scholar 

  18. Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P, Waterfield MD, Ridley A, Downward J. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 1997; 89(3): 457–467

    Article  PubMed  CAS  Google Scholar 

  19. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003; 3(1): 11–22

    Article  PubMed  CAS  Google Scholar 

  20. Albright CF, Giddings BW, Liu J, Vito M, Weinberg RA. Characterization of a guanine nucleotide dissociation stimulator for a ras-related GTPase. EMBO J 1993; 12(1): 339–347

    PubMed  CAS  Google Scholar 

  21. Feig LA. Ral-GTPases: approaching their 15 minutes of fame. Trends Cell Biol 2003; 13(8): 419–425

    Article  PubMed  CAS  Google Scholar 

  22. White MA, Vale T, Camonis JH, Schaefer E, Wigler MH. A role for the Ral guanine nucleotide dissociation stimulator in mediating Rasinduced transformation. J Biol Chem 1996; 271(28): 16439–16442

    Article  PubMed  CAS  Google Scholar 

  23. Urano T, Emkey R, Feig LA. Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation. EMBO J 1996; 15(4): 810–816

    PubMed  CAS  Google Scholar 

  24. Lim KH, O’Hayer K, Adam SJ, Kendall SD, Campbell PM, Der CJ, Counter CM. Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr Biol 2006; 16(24): 2385–2394

    Article  PubMed  CAS  Google Scholar 

  25. Lim KH, Baines AT, Fiordalisi JJ, Shipitsin M, Feig LA, Cox AD, Der CJ, Counter CM. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 2005; 7(6): 533–545

    Article  PubMed  CAS  Google Scholar 

  26. Chien Y, White MA. RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. EMBO Rep 2003; 4(8): 800–806

    Article  PubMed  CAS  Google Scholar 

  27. Parikh C, Subrahmanyam R, Ren R. Oncogenic NRAS rapidly and efficiently induces CMML- and AML-like diseases in mice. Blood 2006; 108(7): 2349–2357

    Article  PubMed  CAS  Google Scholar 

  28. Zhang X, Ren R. Bcr-Abl efficiently induces a myeloproliferative disease and production of excess interleukin-3 and granulocytemacrophage colony-stimulating factor in mice: a novel model for chronic myelogenous leukemia. Blood 1998; 92(10): 3829–3840

    PubMed  CAS  Google Scholar 

  29. Tchevkina E, Agapova L, Dyakova N, Martinjuk A, Komelkov A, Tatosyan A. The small G-protein RalA stimulates metastasis of transformed cells. Oncogene 2005; 24(3): 329–335

    Article  PubMed  CAS  Google Scholar 

  30. Omidvar N, Pearn L, Burnett AK, Darley RL. Ral is both necessary and sufficient for the inhibition of myeloid differentiation mediated by Ras. Mol Cell Biol 2006; 26(10): 3966–3975

    Article  PubMed  CAS  Google Scholar 

  31. Pear WS, Nolan GP, Scott ML, Baltimore D. Production of hightiter helper-free retroviruses by transient transfection. Proc Natl Acad Sci USA 1993; 90(18): 8392–8396

    Article  PubMed  CAS  Google Scholar 

  32. Gross AW, Zhang X, Ren R. Bcr-Abl with an SH3 deletion retains the ability to induce a myeloproliferative disease in mice, yet c-Abl activated by an SH3 deletion induces only lymphoid malignancy. Mol Cell Biol 1999; 19(10): 6918–6928

    PubMed  CAS  Google Scholar 

  33. Pear WS, Miller JP, Xu L, Pui JC, Soffer B, Quackenbush RC, Pendergast AM, Bronson R, Aster JC, Scott ML, Baltimore D. Efficient and rapid induction of a chronic myelogenous leukemialike myeloproliferative disease in mice receiving P210 bcr/abltransduced bone marrow. Blood 1998; 92(10): 3780–3792

    PubMed  CAS  Google Scholar 

  34. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247(4944): 824–830

    Article  PubMed  CAS  Google Scholar 

  35. Joneson T, White MA, Wigler MH, Bar-Sagi D. Stimulation of membrane ruffling and MAP kinase activation by distinct effectors of RAS. Science 1996; 271(5250): 810–812

    Article  PubMed  CAS  Google Scholar 

  36. Hinoi T, Kishida S, Koyama S, Ikeda M, Matsuura Y, Kikuchi A. Post-translational modifications of Ras and Ral are important for the action of Ral GDP dissociation stimulator. J Biol Chem 1996; 271(33): 19710–19716

    Article  PubMed  CAS  Google Scholar 

  37. Matsubara K, Kishida S, Matsuura Y, Kitayama H, Noda M, Kikuchi A. Plasma membrane recruitment of RalGDS is critical for Ras-dependent Ral activation. Oncogene 1999; 18(6): 1303–1312

    Article  PubMed  CAS  Google Scholar 

  38. Plett PA, Frankovitz SM, Orschell CM. Distribution of marrow repopulating cells between bone marrow and spleen early after transplantation. Blood 2003; 102(6): 2285–2291

    Article  PubMed  CAS  Google Scholar 

  39. Fei J, Li Y, Zhu X, Luo X. miR-181a post-transcriptionally downregulates oncogenic RalA and contributes to growth inhibition and apoptosis in chronic myelogenous leukemia (CML). PLoS ONE 2012; 7(3): e32834

    Article  PubMed  CAS  Google Scholar 

  40. Zhu X, Li Y, Luo X, Fei J. Inhibition of small GTPase RalA regulates growth and arsenic-induced apoptosis in chronic myeloid leukemia (CML) cells. Cell Signal 2012; 24(6): 1134–1140

    Article  PubMed  CAS  Google Scholar 

  41. Chu S, Li L, Singh H, Bhatia R. BCR-tyrosine 177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in chronic myelogenous leukemia. Cancer Res 2007; 67(14): 7045–7053

    Article  PubMed  CAS  Google Scholar 

  42. de Bruyn KM, de Rooij J, Wolthuis RM, Rehmann H, Wesenbeek J, Cool RH, Wittinghofer AH, Bos JL. RalGEF2, a pleckstrin homology domain containing guanine nucleotide exchange factor for Ral. J Biol Chem 2000; 275(38): 29761–29766

    Article  PubMed  Google Scholar 

  43. Shao H, Andres DA. A novel RalGEF-like protein, RGL3, as a candidate effector for rit and Ras. J Biol Chem 2000; 275(35): 26914–26924

    PubMed  CAS  Google Scholar 

  44. Wolthuis RM, Bos JL. Ras caught in another affair: the exchange factors for Ral. Curr Opin Genet Dev 1999; 9(1): 112–117

    Article  PubMed  CAS  Google Scholar 

  45. González-García A, Pritchard CA, Paterson HF, Mavria G, Stamp G, Marshall CJ. RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell 2005; 7(3): 219–226

    Article  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Jessica Fredericks

    Present address: EMD Millipore Corporation, 17 Cherry Hill Drive, Danvers, MA, 01923, USA

Authors and Affiliations

  1. State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Jessica Fredericks & Ruibao Ren

  2. Rosenstiel Basic Medical Sciences Research Center and Department of Biology, Brandeis University, Waltham, Massachusetts, 02454, USA

    Jessica Fredericks & Ruibao Ren

Authors
  1. Jessica Fredericks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruibao Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ruibao Ren.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fredericks, J., Ren, R. The role of RAS effectors in BCR/ABL induced chronic myelogenous leukemia. Front. Med. 7, 452–461 (2013). https://doi.org/10.1007/s11684-013-0304-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-013-0304-0

Keywords

Search

Navigation