| First Author | Ta VB | Year | 2012 |
| Journal | J Immunol | Volume | 189 |
| Issue | 10 | Pages | 4842-51 |
| PubMed ID | 23066158 | Mgi Jnum | J:190706 |
| Mgi Id | MGI:5449490 | Doi | 10.4049/jimmunol.1201440 |
| Citation | Ta VB, et al. (2012) Highly restricted usage of Ig H chain VH14 family gene segments in Slp65-deficient pre-B cell leukemia in mice. J Immunol 189(10):4842-51 |
| abstractText | 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-J(H) junctions were diverse, we found highly restricted Ig V(H) gene usage: 55 out of 60 (~92%) leukemias used a V(H)14/SM7-family gene, mainly V(H)14-1 and V(H)14-2. When combined with surrogate or conventional L chains, these V(H)14 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 V(H)14-family rearrangement (10 out of 50) or was in the germline configuration (10 out of 50). V(H)14-1 and V(H)14-2 gene regions differed from their neighboring V(H) 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 V(H) region accessibility at the time of V(H)-to D-J(H) recombination. |
