Ebf1 or PAX5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia

Department of Laboratory Medicine and Pathology, The Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 06/2011; 208(6):1135-49. DOI: 10.1084/jem.20101947
Source: PubMed


As STAT5 is critical for the differentiation, proliferation, and survival of progenitor B cells, this transcription factor may play a role in acute lymphoblastic leukemia (ALL). Here, we show increased expression of activated signal transducer and activator of transcription 5 (STAT5), which is correlated with poor prognosis, in ALL patient cells. Mutations in EBF1 and PAX5, genes critical for B cell development have also been identified in human ALL. To determine whether mutations in Ebf1 or Pax5 synergize with STAT5 activation to induce ALL, we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice heterozygous for Ebf1 or Pax5. Haploinsufficiency of either Pax5 or Ebf1 synergized with Stat5b-CA to rapidly induce ALL in 100% of the mice. The leukemic cells displayed reduced expression of both Pax5 and Ebf1, but this had little effect on most EBF1 or PAX5 target genes. Only a subset of target genes was deregulated; this subset included a large percentage of potential tumor suppressor genes and oncogenes. Further, most of these genes appear to be jointly regulated by both EBF1 and PAX5. Our findings suggest a model whereby small perturbations in a self-reinforcing network of transcription factors critical for B cell development, specifically PAX5 and EBF1, cooperate with STAT5 activation to initiate ALL.

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    • "Somatic mutations and deletions of PAX5 have been found in about 30% of pediatric B ALL samples (79). To date, only haploinsufficiency of PAX5 was shown to be important for induction of leukemia in an activated STAT5 B ALL mouse model (80). "
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    • "The detected aberrations included previously reported loss/gains that are related to ALL, such as 9p13.2 loss involving PAX5 in patient no. 2 [12]; 9p21.3 loss involving CDKN2A in 4 patients (nos. 3, 4, 6 and 7) and MLLT3 in patient no. 3 and 4. "
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