Bone marrow cells in X-linked agammaglobulinemia express pre-B-specific genes (lambda-like and V pre-B) and present immunoglobulin V-D-J gene usage strongly biased to a fetal-like repertoire.

Abstract

Expression of Ig and Ig-related genes has been studied in bone marrow cells from two patients with severe form of X-linked agammaglobulinemia (XLA). Phenotypic analysis revealed the presence of pre-B cells, in the absence of mature B cell markers. The pre-B-specific genes, X-like and V pre-B, were normally transcribed. Sequence analysis of 48 distinct V-D-J cDNA clones directly derived from XLA bone marrow cells indicated that they had characteristics of an early fetal pre-B repertoire. All VH families were identified, with a strong bias in the gene usage: a few VH genes were largely overexpressed, either germline or slightly mutated; most genes had been located 3' of the VH locus and were also used in fetal liver (8-13 wk of gestation). Short D regions, (resulting from D-D fusion, making usage of all D genes in both orientations with utilization of the three reading frames), restricted N diversity, and a fetal JH usage pattern were also observed. Taken together, our data suggest that the XLA defect does not alter V-D-J rearrangements nor the expression of u, X-like, and V pre-B transcripts and most likely results in a poor efficiency of some critical steps of the B cell maturation. (J. Clin. Invest. 1993.91:1616-1629

B precursor acute lymphoblastic leukemia third complementarity‐determining regions predominantly represent an unbiased recombination repertoire: Leukemic transformation frequently occurs in fetal life

“…Therefore, it is possible that antigenic selection in favor of J H~-containing CDR3 regions, takes place at the mature B cell stage of differentiation. In accordance with this hypothesis is the nearly equal usage of J H~ and J H~ in XLA B cells, which have a differentiational block at the end of the pre-B cell stage [47] and the increased J H~ usage in lymphocytes obtained from 8-week fetal liver [42]. However, it should be noted that the appropriate cell population to compare with ALL cells are normal pre-B cells.…”

The Bruton's tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages

“…1). Despite the similar size, a possibility remained that the transcripts in YF and RF were alternatively spliced products of the btk gene,which differ from the btk transcripts of the EBV-positive Burkitt's lymphoma cell line of which the entire cDNA sequence has been reported [5].Therefore, a cDNA library constructed from the RFcell line, was screened with a btk probe and two positive inserts of approximately 2.6 kb were sequenced.The cDNA clones [26,27,29].Yet, the unique features of VHDJH regions in XLA, such as overexpression of particular VH genes, either germline or slightly mutated, restricted N diversity, and a high percentage of unconventional D-to-D fusions [26,27,291, might still argue for a regulatory role of XLA in the Ig gene rearrangement process.…”

The SH3 Domain of Bruton's Tyrosine Kinase Interacts with Vav, Sam68 and EWS

“…The tremendous reduction in the number of B cells can be explained by a failure in pre-B cell production and/or proliferation [4] as well as a defect in the transition of pre-B cells to the immature B cell stage [1,5]. The corresponding altered gene appeared to code for a tyrosine kinase called Bruton's tyrosine kinase (BTK) [6,7].…”