Skip to main content

Advertisement

SpringerLink
Log in

Role of Ras/Raf/MEK/ERK signaling in physiological hematopoiesis and leukemia development

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Recent research on hematological malignancies has shown that malignant cells often co-opt physiological pathways to promote their growth and development. Bone marrow homeostasis requires a fine balance between cellular differentiation and self-renewal; cell survival and apoptosis; and cellular proliferation and senescence. The Ras/Raf/MEK/ERK pathway has been shown to be important in regulating these biological functions. Moreover, the Ras/Raf/MEK/ERK pathway has been estimated to be mutated in 30% of all cancers, thus making it the focus of many scientific studies which have lead to a deeper understanding of cancer development and help to elucidate potential weaknesses that can be targeted by pharmacological agents [1]. In this review, we specifically focus on the role of this pathway in physiological hematopoiesis and how augmentation of the pathway may lead to hematopoietic malignancies. We also discuss the challenges and success of targeting this pathway.

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

Fig. 1

Similar content being viewed by others

References

  1. Bos J. RAS oncogenes in human cancer: a review. Cancer Res. 1989;49:4682–9.

    PubMed  CAS  Google Scholar 

  2. Geest CR, et al. Tight control of MEK-ERK activation is essential in regulating proliferation, survival, and cytokine production of CD34+-derived neutrophil progenitors. Blood. 2009;114(16):3402–12.

    PubMed  CAS  Google Scholar 

  3. Steelman LS, et al. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 2000;18(2):189–218.

    Google Scholar 

  4. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459–65.

    PubMed  CAS  Google Scholar 

  5. Neal SE, et al. Kinetic analysis of the hydrolysis of GTP by p21N-ras. The basal GTPase mechanism. J Biol Chem. 1988;263:19718–22.

    PubMed  CAS  Google Scholar 

  6. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007;7(4):295–308.

    PubMed  CAS  Google Scholar 

  7. Boriack-Sjodin PA, et al. The structural basis of the activation of Ras by Sos. Nature. 1998;394(6691):337–43.

    PubMed  CAS  Google Scholar 

  8. John J, Frech M, Wittinghofer A. Biochemical properties of Ha-ras encoded p21 mutants and mechanism of the autophosphorylation reaction. J Biol Chem. 1988;263:11792–9.

    PubMed  CAS  Google Scholar 

  9. Gibbs JB, et al. Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules. Proc Natl Acad Sci USA. 1984;81:5704–8.

    PubMed  CAS  Google Scholar 

  10. Krengel U, et al. Three-dimensional structures of H-ras p21 mutants: molecular basis for their inability to function as signal switch molecules. Cell. 1990;62(3):539–48.

    PubMed  CAS  Google Scholar 

  11. Scheffzek K, et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science. 1997;277(5324):333–8.

    PubMed  CAS  Google Scholar 

  12. Tong L, et al. Crystal structures at 2.2 Å resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with GDP. J Mol Biol. 1991;217(3):503–16.

    PubMed  CAS  Google Scholar 

  13. Rowell CA, et al. Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J Biol Chem. 1997;272(22):14093–7.

    PubMed  CAS  Google Scholar 

  14. Booden MA, et al. A non-farnesylated Ha-Ras Protein Can Be palmitoylated and trigger potent differentiation and transformation. J Biol Chem. 1999;274(3):1423–31.

    PubMed  CAS  Google Scholar 

  15. Leicht DT, et al. Raf kinases: function, regulation and role in human cancer. Biochim Biophys Acta (BBA) Mol Cell Res. 2007;1773(8):1196–212.

    CAS  Google Scholar 

  16. Pearson G, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22(2):153–83.

    PubMed  CAS  Google Scholar 

  17. Mercer KE, Pritchard CA. Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim Biophys Acta (BBA) Rev Cancer. 2003;1653(1):25–40.

    CAS  Google Scholar 

  18. Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004;4(12):937–47.

    PubMed  CAS  Google Scholar 

  19. Barnier JV, et al. The mouse B-raf gene encodes multiple protein isoforms with tissue-specific expression. J Biol Chem. 1995;270(40):23381–9.

    PubMed  CAS  Google Scholar 

  20. Wu J, et al. Identification and characterization of a new mammalian mitogen-activated protein kinase kinase, MKK2. Mol Cell Biol. 1993;13(8):4539–48.

    PubMed  CAS  Google Scholar 

  21. Bonni A, et al. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science. 1999;286(5443):1358–62.

    PubMed  CAS  Google Scholar 

  22. Zheng CF, Guan KL. Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J Biol Chem. 1993;268(32):23933–9.

    PubMed  CAS  Google Scholar 

  23. Boulton T, et al. An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science. 1990;249(4964):64–7.

    PubMed  CAS  Google Scholar 

  24. Boulton TG, et al. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell. 1991;65(4):663–75.

    PubMed  CAS  Google Scholar 

  25. Gonzalez FA, Raden DL, Davis RJ. Identification of substrate recognition determinants for human ERK1 and ERK2 protein kinases. J Biol Chem. 1991;266(33):22159–63.

    PubMed  CAS  Google Scholar 

  26. Lloyd A. Distinct functions for ERKs? J Biol. 2006;5(5):13.

    PubMed  Google Scholar 

  27. Vantaggiato C, et al. ERK1 and ERK2 mitogen-activated protein kinases affect Ras-dependent cell signaling differentially. J Biol. 2006;5(5):14.

    PubMed  Google Scholar 

  28. Bourcier C, et al. p44 mitogen-activated protein kinase (extracellular signal-regulated kinase 1)–dependent signaling contributes to epithelial skin carcinogenesis. Cancer Res. 2006;66(5):2700–7.

    PubMed  CAS  Google Scholar 

  29. Marchi M, et al. The N-terminal domain of ERK1 accounts for the functional differences with ERK2. PLoS ONE. 2008;3(12):e3873.

    PubMed  Google Scholar 

  30. Voisin L, et al. Genetic demonstration of a redundant role of extracellular signal-regulated kinase 1 (ERK1) and ERK2 mitogen-activated protein kinases in promoting fibroblast proliferation. Mol Cell Biol. 2010;30(12):2918–32.

    PubMed  CAS  Google Scholar 

  31. Marais R, et al. Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic Ras and tyrosine kinases. J Biol Chem. 1997;272(7):4378–83.

    PubMed  CAS  Google Scholar 

  32. Khosravi-Far R, et al. Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol. 1996;16(7):3923–33.

    PubMed  CAS  Google Scholar 

  33. Weber CK, et al. Mitogenic signaling of Ras is regulated by differential interaction with Raf isozymes. Oncogene. 2000;19:169–76.

    PubMed  CAS  Google Scholar 

  34. Yan J, et al. Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J Biol Chem. 1998;273(37):24052–6.

    PubMed  CAS  Google Scholar 

  35. Rodriguez-Viciana P, et al. Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation. EMBO J. 1996;15:2442–51.

    PubMed  CAS  Google Scholar 

  36. Catling A, et al. A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function. Mol Cell Biol. 1995;15(10):5214–25.

    PubMed  CAS  Google Scholar 

  37. Papin C, et al. Modulation of kinase activity and oncogenic properties by alternative splicing reveals a novel regulatory mechanism for B-Raf. J Biol Chem. 1998;273(38):24939–47.

    PubMed  CAS  Google Scholar 

  38. Pritchard C, et al. Conditionally oncogenic forms of the A-Raf and B-Raf protein kinases display different biological and biochemical properties in NIH 3T3 cells. Mol Cell Biol. 1995;15(11):6430–42.

    PubMed  CAS  Google Scholar 

  39. Papin C, et al. Identification of signalling proteins interacting with B-Raf in the yeast two-hybrid system. Oncogene. 1996;12:2213–21.

    PubMed  CAS  Google Scholar 

  40. Mercer K, et al. ERK signaling and oncogenic transformation are not impaired in cells lacking A-Raf. Oncogene. 2002;17:347–55.

    Google Scholar 

  41. Wan PTC, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855–67.

    PubMed  CAS  Google Scholar 

  42. Garnett MJ, et al. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol cell. 2005;20(6):963–9.

    PubMed  CAS  Google Scholar 

  43. Rushworth LK, et al. Regulation and role of Raf-1/B-Raf heterodimerization. Mol Cell Biol. 2006;26(6):2262–72.

    PubMed  CAS  Google Scholar 

  44. Farrar MA, Alberola-lla J, Perlmutter RM. Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization. Nature. 1996;383:178–81.

    PubMed  CAS  Google Scholar 

  45. Luo Z, et al. Oligomerization activates c-Raf-1 through a Ras-dependent mechanism. Nature. 1996;383:181–5.

    PubMed  CAS  Google Scholar 

  46. Mizutani S, et al. Involvement of B-Raf in Ras-induced Raf-1 activation. FEBS Lett. 2001;507(3):295–8.

    PubMed  CAS  Google Scholar 

  47. Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science. 1999;286(5445):1741–4.

    PubMed  CAS  Google Scholar 

  48. Rommel C, et al. Differentiation stage-specific Inhibition of the Raf-MEK-ERK pathway by Akt. Science. 1999;286(5445):1738–41.

    PubMed  CAS  Google Scholar 

  49. Moelling K, et al. Regulation of Raf-Akt cross-talk. J Biol Chem. 2002;277(34):31099–106.

    PubMed  CAS  Google Scholar 

  50. Zhang B-H, et al. Serum- and glucocorticoid-inducible kinase SGK phosphorylates and negatively regulates B-Raf. J Biol Chem. 2001;276(34):31620–6.

    PubMed  CAS  Google Scholar 

  51. Guan K-L, et al. Negative regulation of the serine/threonine kinase B-Raf by Akt. J Biol Chem. 2000;275(35):27354–9.

    PubMed  CAS  Google Scholar 

  52. Jelinek T, et al. RAS and RAF-1 form a signalling complex with MEK-1 but not MEK-2. Mol Cell Biol. 1994;14(12):8212–8.

    PubMed  CAS  Google Scholar 

  53. Lowy DR, Willumsen BM. Function and regulation of RAS. Annu Rev Biochem. 1993;62(1):851–91.

    PubMed  CAS  Google Scholar 

  54. Esteban LM, et al. Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development. Mol Cell Biol. 2001;21(5):1444–52.

    PubMed  CAS  Google Scholar 

  55. Johnson L, et al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev. 1997;11:2468–81.

    PubMed  CAS  Google Scholar 

  56. Umanoff H, et al. The murine N-ras gene is not essential for growth and development. Proc Natl Acad Sci USA. 1995;92(5):1709–13.

    PubMed  CAS  Google Scholar 

  57. Pritchard CA, et al. Post-natal lethality and neurological and gastrointestinal defects in mice with targeted disruption of the A-Raf protein kinase gene. Curr Biol CB. 1996;6(5):614–7.

    CAS  Google Scholar 

  58. Wojnowski L, et al. Endothelial apoptosis in Braf-deficient mice. Nat Genet. 1997;16(3):293–7.

    PubMed  CAS  Google Scholar 

  59. Wiese S, et al. Specific function of B-Raf in mediating survival of embryonic motoneurons and sensory neurons. Nat Neurosci. 2001;4(2):137–42.

    PubMed  CAS  Google Scholar 

  60. Wojnowski L, et al. Craf-1 protein kinase is essential for mouse development. Mech Dev. 1998;76:141–9.

    PubMed  CAS  Google Scholar 

  61. Mikula M, et al. Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. EMBO J. 2001;20(8):1952–62.

    PubMed  CAS  Google Scholar 

  62. Huser M, et al. MEK kinase activity is not necessary for Raf-1 function. EMBO J. 2001;20(8):1940–51.

    PubMed  CAS  Google Scholar 

  63. Niault TS, Baccarini M. Targets of Raf in tumorigenesis. Carcinogenesis. 2010;31(7):1165–74.

    PubMed  CAS  Google Scholar 

  64. Wojnowski L, et al. Overlapping and specific functions of Braf and Craf-1 proto-oncogenes during mouse embryogenesis. Mech Dev. 2000;91(1–2):97–104.

    PubMed  CAS  Google Scholar 

  65. Brott B, et al. MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues. Cell Growth Differ. 1993;4(11):921–9.

    PubMed  CAS  Google Scholar 

  66. Alessandrini A, Brott B, Erikson R. Differential expression of MEK1 and MEK2 during mouse development. Cell Growth Differ. 1997;8(5):505–11.

    PubMed  CAS  Google Scholar 

  67. Giroux S, et al. Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr Biol CB. 1999;9(7):369–76.

    CAS  Google Scholar 

  68. Bissonauth V, et al. Requirement for Map2k1 (Mek1) in extra-embryonic ectoderm during placentogenesis. Development. 2006;133(17):3429–40.

    PubMed  CAS  Google Scholar 

  69. Belanger L-F, et al. Mek2 is dispensable for mouse growth and development. Mol Cell Biol. 2003;23(14):4778–87.

    PubMed  CAS  Google Scholar 

  70. Scholl FA, et al. Mek1/2 MAPK kinases are essential for mammalian development, homeostasis, and Raf-induced hyperplasia. Dev Cell. 2007;12(4):615–29.

    PubMed  CAS  Google Scholar 

  71. Pages G, et al. Defective thymocyte maturation in p44 MAP kinase (ERk1) knockout mice. Science. 1999;286:1374–7.

    PubMed  CAS  Google Scholar 

  72. Saba-El-Leil MK, et al. An essential function of the mitogen-activated protein Erk2 in mouse trophoblast development. EMBO Reports. 2003;4:964–8.

    PubMed  CAS  Google Scholar 

  73. Hatano N, et al. Essential role for ERK2 mitogen-activated protein kinase in placental development. Genes Cells. 2003;8(11):847–56.

    PubMed  CAS  Google Scholar 

  74. Weissman IL, Anderson DJ, Gage F. Stem and progenitor cells: origins. phenotypes, lineage commitments, and transdifferentiations. Ann Rev Cell Dev Biol. 2001;17(1):387–403.

    CAS  Google Scholar 

  75. Davies H, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.

    PubMed  CAS  Google Scholar 

  76. Oostendorp RA, et al. Oncostatin M-mediated regulation of KIT-ligand-induced extracellular signal-regulated kinase signaling maintains hematopoietic repopulating activity of Lin−CD34+CD133+ cord blood cells. Stem Cells. 2008;26(8):2164–72.

    PubMed  CAS  Google Scholar 

  77. Watowich SS, et al. Cytokine receptor signal transduction and the control of hematopoietic cell development. Ann Rev Cell Dev Biol. 1996;12(1):91–128.

    CAS  Google Scholar 

  78. Hsu C-L, Kikuchi K, Kondo M. Activation of mitogen-activated protein kinase kinase (MEK)/extracellular signal regulated kinase (ERK) signaling pathway is involved in myeloid lineage commitment. Blood. 2007;110(5):1420–8.

    PubMed  CAS  Google Scholar 

  79. Kondo M, et al. Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines. Nature. 2000;407(6802):383–6.

    PubMed  CAS  Google Scholar 

  80. de Groot RP, Coffer PJ, Koenderman L. Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family. Cell Signal. 1998;10(9):619–28.

    PubMed  Google Scholar 

  81. Hu X, et al. Prolonged activation of the mitogen-activated protein kinase pathway is required for macrophage-like differentiation of a human myeloid leukemic cell line. Cell Growth Differ. 2000;11(4):191–200.

    PubMed  CAS  Google Scholar 

  82. Hara T, Miyajima A. Function and signal transduction mediated by the interleukin 3 receptor system in hematopoiesis. Stem Cells. 1996;14(6):605–18.

    PubMed  CAS  Google Scholar 

  83. Miranda MB, et al. Cytokine-induced myeloid differentiation is dependent on activation of the MEK/ERK pathway. Leukemia Res. 2005;29(11):1293–306.

    CAS  Google Scholar 

  84. Miranda MB, McGuire TF, Johnson DE. Importance of MEK-1/-2 signaling in monocytic and granulocytic differentiation of myeloid cell lines. Leukemia. 2002;16:683–92.

    PubMed  CAS  Google Scholar 

  85. Kamata T, et al. A critical function for B-Raf at multiple stages of myelopoiesis. Blood. 2005;106(3):833–40.

    PubMed  CAS  Google Scholar 

  86. Fichelson S, et al. Megakaryocyte growth and development factor-induced proliferation and differentiation are regulated by the mitogen-activated protein kinase pathway in primitive cord blood hematopoietic progenitors. Blood. 1999;94(5):1601–13.

    PubMed  CAS  Google Scholar 

  87. Sui X, et al. Synergistic activation of MAP Kinase (ERK1/2) by erythropoietin and stem cell factor is essential for expanded erythropoiesis. Blood. 1998;92(4):1142–9.

    PubMed  CAS  Google Scholar 

  88. Miyazaki R, Ogata H, Kobayashi Y. Requirement of thrombopoietin-induced activation of ERK for megakarocyte differentiation and of p38 for erythroid differentiation. Ann Hematol. 2001;80:284–91.

    PubMed  CAS  Google Scholar 

  89. Rouyez M, et al. Control of thrombopoietin-induced megakaryocytic differentiation by the mitogen-activated protein kinase pathway. Mol Cell Biol. 1997;17(9):4991–5000.

    PubMed  CAS  Google Scholar 

  90. Rojnuckarin P, Drachman JG, Kaushansky K. Thrombopoietin-induced activation of the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes: role in endomitosis. Blood. 1999;94(4):1273–82.

    PubMed  CAS  Google Scholar 

  91. SÉVerin S, Ghevaert C, Mazharian A. The mitogen-activated protein kinase signaling pathways: role in megakaryocyte differentiation. J Thromb Haemost. 2010;8(1):17–26.

    PubMed  Google Scholar 

  92. Kamata T, Pritchard CA, Leavitt AD. Raf-1 is not required for megakaryocytopoiesis or TPO-induced ERK phosphorylation. Blood. 2004;103:2568–70.

    PubMed  CAS  Google Scholar 

  93. Mazharian A, Watson SP, Séverin S. Critical role for ERK1/2 in bone marrow and fetal liver-derived primary megakaryocyte differentiation, motility, and proplatelet formation. Exp Hematol. 2009;37(10):1238.e5–1249.e5.

    Google Scholar 

  94. Zhang J, Lodish HF. Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors. Blood. 2004;104(6):1679–87.

    PubMed  CAS  Google Scholar 

  95. Zhang J, Lodish HF. Identification of K-ras as the major regulator for cytokine-dependent Akt activation in erythroid progenitors in vivo. Proc Natl Acad Sci USA. 2005;102(41):14605–10.

    PubMed  CAS  Google Scholar 

  96. Darley RL, et al. Protein kinase C mediates mutant N-Ras-induced developmental abnormalities in normal human erythroid cells. Blood. 2002;100(12):4185–92.

    PubMed  CAS  Google Scholar 

  97. Guihard S, et al. The MAPK ERK1 is a negative regulator of the adult steady-state splenic erythropoiesis. Blood. 2010;115(18):3686–94.

    PubMed  CAS  Google Scholar 

  98. Zebisch A, et al. Two transforming C-RAF germ-line mutations identified in patients with therapy-related acute myeloid leukemia. Cancer Res. 2006;66(7):3401–8.

    PubMed  CAS  Google Scholar 

  99. Swan KA, et al. Involvement of p21ras distinguishes positive and negative selection in thymocytes. EMBO J. 1995;14:276–85.

    PubMed  CAS  Google Scholar 

  100. Alberola-lla J, et al. Positive and negative selection invoke distinct signaling pathways. J Exp Med. 1996;184:9–18.

    Google Scholar 

  101. Crompton T, Gilmour KC, Owen MJ. The MAP kinase pathway controls differentiation from double-negative to double-positive thymocyte. Cell. 1996;86(2):243–51.

    PubMed  CAS  Google Scholar 

  102. Alberola-lla J, et al. Selective requirement for MAP kinase activation in thymocyte differentiation. Nature. 1995;373(6515):620–3.

    Google Scholar 

  103. Swat W, et al. Activated Ras signals differentiation and expansion of CD4+8+ thymocytes. Proc Natl Acad Sci USA. 1996;93(10):4683–7.

    PubMed  CAS  Google Scholar 

  104. Bommhardt U, et al. Activation of the extracellular signal-related kinase/mitogen-activated protein kinase pathway discriminates CD4 versus CD8 lineage commitment in the thymus. J Immunol. 1999;163(2):715–22.

    PubMed  CAS  Google Scholar 

  105. Fischer AM, et al. The role of Erk1 and Erk2 in multiple stages of T cell development. Immunity. 2005;23(4):431–43.

    PubMed  CAS  Google Scholar 

  106. Sharp LL, et al. The influence of the MAPK pathway on T cell lineage commitment. Immunity. 1997;7(5):609–18.

    PubMed  CAS  Google Scholar 

  107. Sugawara T, et al. Differential roles of ERK and p38 MAP kinase pathways in positive and negative selection of T lymphocytes. Immunity. 1998;9(4):565–74.

    PubMed  CAS  Google Scholar 

  108. Bommhardt U, et al. MEK activity regulates negative selection of immature CD4+CD8+ thymocytes. J Immunol. 2000;164(5):2326–37.

    PubMed  CAS  Google Scholar 

  109. Mariathasan S, et al. Degree of ERK activation influences both positive and negative thymocyte selection. Eur J Immunol. 2000;30(4):1060–8.

    PubMed  CAS  Google Scholar 

  110. Land H, Parada LF, Weinberg RA. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983;304:596–602.

    PubMed  CAS  Google Scholar 

  111. Kamijo T, et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19 ARF. Cell. 1997;91(5):649–59.

    PubMed  CAS  Google Scholar 

  112. Serrano M, et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88(5):593–602.

    PubMed  CAS  Google Scholar 

  113. Ruley HE. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature. 1983;304:602–6.

    PubMed  CAS  Google Scholar 

  114. Tanaka N, et al. Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1. Cell. 1994;77(6):829–39.

    PubMed  CAS  Google Scholar 

  115. Zindy F, et al. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 1998;12(15):2424–33.

    PubMed  CAS  Google Scholar 

  116. Zhu J, et al. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev. 1998;12(19):2997–3007.

    PubMed  CAS  Google Scholar 

  117. Lin AW, et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 1998;12(19):3008–19.

    PubMed  CAS  Google Scholar 

  118. Tuveson DA, et al. Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004;5(4):375–87.

    PubMed  CAS  Google Scholar 

  119. Guerra C, et al. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell. 2003;4(2):111–20.

    PubMed  CAS  Google Scholar 

  120. Berns A. Cancer: improved mouse models. Nature. 2001;410(6832):1043–4.

    PubMed  CAS  Google Scholar 

  121. Braun BS, et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci USA. 2004;101(2):597–602.

    PubMed  CAS  Google Scholar 

  122. Sabnis AJ, et al. Oncogenic Kras initiates leukemia in hematopoietic stem cells. PLoS Biol. 2009;7(3):e1000059.

    Google Scholar 

  123. Braun BS, et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci USA. 2004;101:597–602.

    PubMed  CAS  Google Scholar 

  124. Van Meter MEM, et al. K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells. Blood. 2007;109(9):3945–52.

    PubMed  Google Scholar 

  125. Zhang J, et al. Oncogenic Kras-induced leukemogenesis: hematopoietic stem cells as the initial target and lineage-specific progenitors as the potential targets for final leukemic transformation. Blood. 2009;113(6):1304–14.

    PubMed  CAS  Google Scholar 

  126. Braun BS, et al. Somatic activation of a conditional KrasG12D allele causes ineffective erythropoiesis in vivo. Blood. 2006;108(6):2041–4.

    PubMed  CAS  Google Scholar 

  127. Zhang J, et al. Expression of oncogenic K-ras from its endogenous promoter leads to a partial block of erythroid differentiation and hyperactivation of cytokine-dependent signaling pathways. Blood. 2007;109(12):5238–41.

    PubMed  CAS  Google Scholar 

  128. Zhang J, Lodish HF. Endogenous K-ras signaling in erythroid differentiation. Cell Cycle. 2007;6:1970–3.

    PubMed  CAS  Google Scholar 

  129. von Lintig FC, et al. Ras activation in normal white blood cells and childhood acute lymphoblastic leukemia. Clin Cancer Res. 2000;6(5):1804–10.

    Google Scholar 

  130. Bos J, et al. Mutations in N-ras predominate in acute myeloid leukemia. Blood. 1987;69(4):1237–41.

    PubMed  CAS  Google Scholar 

  131. Miyauchi J, et al. Mutations of the N-ras gene in juvenile chronic myelogenous leukemia. Blood. 1994;83(8):2248–54.

    PubMed  CAS  Google Scholar 

  132. Janssen JW, et al. RAS gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes. Proc Natl Acad Sci USA. 1987;84(24):9228–32.

    PubMed  CAS  Google Scholar 

  133. Parikh C, Subrahmanyam R, Ren R. Oncogenic NRAS rapidly and efficiently induces CMML- and AML-like diseases in mice. Blood. 2006;108(7):2349–57.

    PubMed  CAS  Google Scholar 

  134. MacKenzie KL, et al. Mutant N-ras induces myeloproliferative disorders and apoptosis in bone marrow repopulated mice. Blood. 1999;93(6):2043–56.

    PubMed  CAS  Google Scholar 

  135. Iida M, et al. Lack of constitutive action of MAP kinase pathway in human acute myeloid leukemia cells with N-Ras mutation. Leukemia. 1999;13:585–9.

    PubMed  CAS  Google Scholar 

  136. Aoki Y, et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005;37(10):1038–40.

    PubMed  CAS  Google Scholar 

  137. Parikh C, Subrahmanyam R, Ren R. Oncogenic NRAS, KRAS, and HRAS exhibit different leukemogenic potentials in mice. Cancer Res. 2007;67(15):7139–46.

    PubMed  CAS  Google Scholar 

  138. Hoyle PE, et al. Differential abilities of the Raf family of protein kinases to abrogate cytokine dependency and prevent apoptosis in murine hematopoietic cells by a MEK1-dependent mechanism. Leukemia. 2000;14:642–56.

    PubMed  CAS  Google Scholar 

  139. McCubrey JA, et al. Differential abilities of activated Raf oncoproteins to abrogate cytokine dependency, prevent apoptosis and induce autocrine growth factor synthesis in human hematopoietic cells. Leukemia. 1998;12:1903–29.

    PubMed  CAS  Google Scholar 

  140. Mercer K, et al. Expression of endogenous oncogenic V600EB-raf induces proliferation and developmental defects in mice and transformation of primary fibroblasts. Cancer Res. 2005;65(24):11493–500.

    PubMed  CAS  Google Scholar 

  141. Emuss V, et al. Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF. Cancer Res. 2005;65(21):9719–26.

    PubMed  CAS  Google Scholar 

  142. Blalock WL, et al. Effects of inducible MEK1 activation on the cytokine dependency of lymphoid cells. Leukemia. 2001;15:794–807.

    PubMed  CAS  Google Scholar 

  143. Blalock WL, et al. A conditionally-active form of MEK1 results in autocrine transformation of human and mouse hematopoietic cells. Oncogene. 2000;19:526–36.

    PubMed  CAS  Google Scholar 

  144. Mansour SJ, et al. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science. 1994;265:966–70.

    PubMed  CAS  Google Scholar 

  145. Ricciardi MR, et al. Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia. Leukemia. 2005;19(9):1543–9.

    PubMed  CAS  Google Scholar 

  146. Towatari M, et al. Constitutive activation of mitogen-activated protein kinase pathway in acute leukemia cells. Leukemia. 1997;11:479–84.

    PubMed  CAS  Google Scholar 

  147. Gregorj C, et al. ERK1/2 phosphorylation is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia. Blood. 2007;109(12):5473–6.

    PubMed  CAS  Google Scholar 

  148. Reuter CWM, Morgan MA, Bergmann L. Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Blood. 2000;96(5):1655–69.

    PubMed  CAS  Google Scholar 

  149. Morgan MA, et al. Synergistic cytotoxic effects in myeloid leukemia cells upon cotreatment with farnesyltransferase and geranylgeranyl transferase-I inhibitors. Leukemia. 2003;17(8):1508–20.

    PubMed  CAS  Google Scholar 

  150. Dudley DT, et al. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA. 1995;92(17):7686–9.

    PubMed  CAS  Google Scholar 

  151. Alessi DR, et al. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem. 1995;270(46):27489–94.

    PubMed  CAS  Google Scholar 

  152. Favata MF, et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 1998;273(29):18623–32.

    PubMed  CAS  Google Scholar 

  153. Morgan MA, Dolp O, Reuter CWM. Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. Blood. 2001;97(6):1823–34.

    PubMed  CAS  Google Scholar 

  154. Milella M, et al. Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. J Clin Invest. 2001;108(6):851–9.

    PubMed  CAS  Google Scholar 

  155. Davies SP, et al. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000;351(1):95–105.

    PubMed  CAS  Google Scholar 

  156. LoRusso PM, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol. 2005;23(23):5281–93.

    PubMed  CAS  Google Scholar 

  157. Sebolt-Leopold JS, et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med. 1999;5(7):810–6.

    PubMed  CAS  Google Scholar 

  158. Lunghi P, et al. Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts. Leukemia. 2003;17:1783–93.

    PubMed  CAS  Google Scholar 

  159. Sebolt-Leopold JS. Advances in the development of cancer therapeutics directed against the RAS-mitogen-activated protein kinase pathway. Clin Cancer Res. 2008;14(12):3651–6.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Immunology, Duke University Medical Center, 101 Jones Building, DUMC Box 3010, Research Drive, Durham, NC, 27710, USA

    Eva Chung & Motonari Kondo

Authors
  1. Eva Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Motonari Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Motonari Kondo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chung, E., Kondo, M. Role of Ras/Raf/MEK/ERK signaling in physiological hematopoiesis and leukemia development. Immunol Res 49, 248–268 (2011). https://doi.org/10.1007/s12026-010-8187-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-010-8187-5

Keywords

Search

Navigation