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

Abstract

To determine whether the ALL (acute lymphoblastic leukemia) CDR3 (third complementarity-determining region) repertoire represents the recombination repertoire, or shows evidence of selectional processes inherent to normal B cell differentiation or malignant transformation, we analyzed 68 ALL CDR3 regions and included 127 previously published sequences in the analyses. We found no evidence of selection prior to malignant transformation as recombination was random with 1/3 "in frame" and 2/3 "out of frame" joinings and usage of all three D reading frames was observed. D and JH gene segments were predominantly unmutated which allowed a detailed analysis of gene usage and rearrangement characteristics. JH4 and JH6 usage (both 32.2%) was significantly different (p = 0.005) from that observed in peripheral B lymphocytes. D gene family usage roughly represented D gene family size with the exception of the DXP and DA/K family which were over- and underrepresented (p = < or = 0.05), respectively. D-D fusions were found in 26.2% of CDR3 regions. If less stringent criteria were applied DIR homology was found in 40/65 sequences, suggesting the frequent involvement of DIR gene segments in human CDR3 formation. The rearranged D genes were evenly distributed over the D locus, suggesting that D recombination is a predominantly random process, independent of physical location at the locus. Also, there was no correlation between JH gene usge and physical location of the rearranged D gene segment, which excludes a major contribution of the DJH replacement recombination mechanism. In 36.1% of CDR3 regions N-nucleotides at the DJH junction were absent. This frequency is higher than observed for peripheral B lymphocytes. It is suggested that for a number of ALL the initial transformational event took place in early fetal life. We conclude that ALL CDR3 sequences show no evidence of selection prior to malignant transformation, nor of extensive changes subsequent to malignant transformation.

Prenatal origin of childhood acute lymphoblastic leukemia, association with birth weight and hyperdiploidy

“…5 Further evidence for an in utero leukemic transformation comes from the predominance of fetal type D-J joining of the immunoglobulin H (IgH) heavy-chain genes in young children with B-precursor ALL. 6,7 The detection of concordant leukemia in monozygotic twins, [8][9][10][11][12][13] strongly supports the hypothesis that leukemogenesis may be initiated in utero. The only plausible explanation for concordant leukemia in monozygotic twins is that the transformed cell in one twin spreads to the other twin, presumably by vascular anastomoses that exist within shared monochorionic placentas.…”

The use of monoclonal gene rearrangement for detection of minimal residual disease in acute lymphoblastic leukemia of childhood

“…might be able to identify patients who were relapsing, particularly if monoclonality had not been present in an earlier This patient was a typical example of the problem associated with scoring detection of a faint monoclonal band against a specimen. However, clonal evolution, which occurs frequently during treatment, [20][21][22][23] could confound the use of polyclonal background. In patient 497 there were four monoclonal bands at diagnosis, two of which were present at day detection of monoclonality if it resulted in replacement of a well amplified gene rearrangement by a poorly amplified one.…”

Leukemia-associated genetic aberrations in mesenchymal stem cells of children with acute lymphoblastic leukemia

“…In addition to the TEL-AML fusion gene, SV40-Tag MSC from patient 5 showed abnormal numbers of chromosomes 12 and 21 in some cases (Figure 26). The first two types showed a standard number of chromosomes (44)(45)(46).…”