Highly restricted usage of ig H chain VH14 family gene segments in Slp65-deficient Pre-B cell leukemia in mice

Mice deficient for the adapter protein Slp65 (also known as Blnk), a key component in precursor-BCR (pre-BCR) signaling, spontaneously develop pre-B cell leukemia. In these leukemias, proliferation is thought to be driven by constitutive Jak3/Stat5 signaling, mostly due to autocrine production of IL-7, together with high surface expression of the pre-BCR. In this study, we investigated whether particular IgH specificities would predispose Slp65-deficient pre-B cells to malignant transformation. Whereas V H-D-JH junctions were diverse, we found highly restricted Ig VH gene usage: 55 out of 60 (¡«92%) leukemias used a VH14/SM7-family gene, mainly VH14-1 and VH14-2. When combined with surrogate or conventional L chains, these VH14 IgH chains did not provide increased proliferative signals or exhibit enhanced poly-or autoreactivity. We therefore conclude that pre-BCR specificity per se did not contribute to oncogenic transformation. Remarkably, in a high proportion of Slp65-deficient leukemias, the nonexpressed IgH allele also harbored a VH14-family rearrangement (10 out of 50) or was in the germline configuration (10 out of 50). VH14-1 and VH14-2 gene regions differed from their neighboring VH genes in that they showed active H3K4me3 histone modification marks and germline transcription at the pro-B cell stage in Rag1-deficient mice. Taken together, these findings demonstrate that in Slp65-deficient mice, malignant transformation is largely limited to particular pre-B cells that originate from pro-B cells that had restricted IgH VH region accessibility at the time of V H-to D-JH recombination. Copyright

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