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Deletion of genes encoding PU.1 and Spi-B in B cells impairs differentiation and induces pre-B cell acute lymphoblastic leukemia

Kristen M. Sokalski, Stephen K.H. Li, Ian Welch, Heather-Anne T. Cadieux-Pitre, Marek R. Gruca, Rodney P. DeKoter

Abstract

The E26-transformation specific (Ets) transcription factor PU.1 is required to generate lymphoid progenitor cells from hematopoietic stem cells, but is not required to generate B cells from committed B lineage progenitors. We hypothesized that PU.1 function in B cell differentiation is complemented by the related Ets transcription factor Spi-B. To test this hypothesis, mice were generated lacking both PU.1 and Spi-B in the B cell lineage. Unlike mice lacking PU.1 or Spi-B, mice deficient in both PU.1 and Spi-B in the B cell lineage had reduced frequencies of B cells as well as impaired B cell differentiation. Strikingly, all PU.1 and Spi-B-deficient mice developed pre-B cell acute lymphoblastic leukemia before 30 weeks of age. Pre-B cells accumulated in the thymus resulting in massive thymic enlargement and dyspnea. These findings demonstrate that PU.1 and Spi-B are essential transcriptional regulators of B cell differentiation as well as novel tumor suppressors in the B cell lineage.

  • Submitted February 7, 2011.
  • Accepted June 13, 2011.