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-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.
Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam 3000 CA, The Netherlands.
Van B T
VB
Ta
Marjolein J W
MJ
de Bruijn
Louise
L
Matheson
Markus
M
Zoller
Martina P
MP
Bach
Hedda
H
Wardemann
Hassan
H
Jumaa
Anne
A
Corcoran
Rudi W
RW
Hendriks
D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000818:Animals; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology*; D015851:Interleukin-7 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D015851:Interleukin-7