A Flt3- and Ras-dependent pathway primes B cell development by inducing a state of IL-7 responsiveness

J Immunol. 2010 Feb 15;184(4):1728-36. doi: 10.4049/jimmunol.0903023. Epub 2010 Jan 11.


Ras plays an important role in B cell development. However, the stage at which Ras governs B cell development remains unclear. Moreover, the upstream receptors and downstream effectors of Ras that govern B cell differentiation remain undefined. Using mice that express a dominant-negative form of Ras, we demonstrate that Ras-mediated signaling plays a critical role in the development of common lymphoid progenitors. This developmental block parallels that found in flt3(-/-) mice, suggesting that Flt3 is an important upstream activator of Ras in early B cell progenitors. Ras inhibition impaired proliferation of common lymphoid progenitors and pre-pro-B cells but not pro-B cells. Rather, Ras promotes STAT5-dependent pro-B cell differentiation by enhancing IL-7Ralpha levels and suppressing socs2 and socs3 expression. Our results suggest a model in which Flt3/Ras-dependent signals play a critical role in B cell development by priming early B cell progenitors for subsequent STAT5-dependent B cell differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cell Lineage / genetics
  • Cell Lineage / immunology
  • Gene Knock-In Techniques
  • Humans
  • Interleukin-7 / physiology*
  • Lymphoid Progenitor Cells / cytology
  • Lymphoid Progenitor Cells / immunology
  • Lymphoid Progenitor Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • STAT5 Transcription Factor / physiology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • fms-Like Tyrosine Kinase 3 / deficiency
  • fms-Like Tyrosine Kinase 3 / genetics
  • fms-Like Tyrosine Kinase 3 / physiology*
  • ras Proteins / genetics
  • ras Proteins / physiology*


  • Interleukin-7
  • STAT5 Transcription Factor
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3
  • ras Proteins