Presence of N regions in the clonotypic DJ rearrangements of the immunoglobulin heavy-chain genes indicates an exquisitely short latency in t(4;11)-positive infant acute lymphoblastic leukemia

Blood ◽  
2001 ◽  
Vol 98 (7) ◽  
pp. 2272-2274 ◽  
Author(s):  
Karin Fasching ◽  
Simon Panzer ◽  
Oskar A. Haas ◽  
Arndt Borkhardt ◽  
Rolf Marschalek ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Heavy Chain ◽  
Lymphoblastic Leukemia ◽  
Latency Period ◽  
Immunoglobulin Heavy Chain ◽  
In Utero ◽  
Cell Precursor ◽  
Developmentally Regulated ◽  
Igh Genes ◽  
Immunoglobulin Heavy Chain Genes

Childhood acute lymphoblastic leukemia (ALL) is frequently initiated in utero at a time of developmentally regulated insertion of N regions into the DJH rearrangements of immunoglobulin heavy-chain (IgH) genes. Here it is shown that N regions are present in the clonotypic DJH rearrangements in 11 of 12 infant ALLs with t(4;11). These data are compared with the 122 previously published DJH sequences and were found to have a pattern similar to that of ALL in children older than 3 years at diagnosis but were unlike that in children younger than 3 years who predominantly lack N regions. These findings, therefore, indicate that t(4;11)-positive infant ALL is initiated later in fetal development than most B-cell precursor ALL from children younger than 3 years and that they have a shorter latency period already in utero.

scholarly journals Rearrangement of immunoglobulin heavy chain genes in T cell acute lymphoblastic leukemia

Blood ◽  
1985 ◽  
Vol 65 (3) ◽  
pp. 725-729 ◽  
Author(s):  
GR Kitchingman ◽  
U Rovigatti ◽  
AM Mauer ◽  
S Melvin ◽  
SB Murphy ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Heavy Chain ◽  
Germ Line ◽  
Lymphoblastic Leukemia ◽  
Immunoglobulin Heavy Chain ◽  
Chain Gene ◽  
Heavy Chain Gene ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Immunoglobulin Heavy Chain Genes

Abstract We studied the arrangement of the immunoglobulin heavy chain genes by Southern blot analysis of DNA freshly obtained from marrow blast cells of 14 children with T cell acute lymphoblastic leukemia (T-ALL) using probes to the C mu and JH gene segments: At least one of the C mu-gene alleles was rearranged in three cases. In two of these, one C mu gene had the germ-line configuration and one was rearranged, whereas both alleles were rearranged in the third case. In one case, a rearranged heavy chain gene hybridized to the C mu-region probe, but not to the JH probe, indicating that the entire JH region had been deleted. These results demonstrate that immunoglobulin heavy chain gene rearrangements are not restricted to B lineage lymphoproliferative diseases in humans.

Immunoglobulin heavy chain locus chromosomal translocations in B-cell precursor acute lymphoblastic leukemia: rare clinical curios or potent genetic drivers?

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1490-1499 ◽  
Author(s):  
Martin J. S. Dyer ◽  
Takashi Akasaka ◽  
Melania Capasso ◽  
Palminder Dusanjh ◽  
Yin Fai Lee ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Heavy Chain ◽  
Lymphoblastic Leukemia ◽  
Clinical Importance ◽  
B Cell Lymphoma ◽  
Immunoglobulin Heavy Chain ◽  
Chromosomal Translocations ◽  
Cell Precursor ◽  
Genomic Deletions

Abstract Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus define common subgroups of B-cell lymphoma but are rare in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Recent fluorescent in situ hybridization and molecular cloning studies have identified several novel IGH translocations involving genes that play important roles in normal hemopoiesis, including the cytokine receptor genes CRLF2 and EPOR, all members of the CCAAT enhancer-binding protein gene family, as well as genes not normally expressed in hemopoietic cells including inhibitor of DNA binding 4. IGH translocation results in deregulated target gene expression because of juxtaposition with IGH transcriptional enhancers. However, many genes targeted by IGH translocations are also more commonly deregulated in BCP-ALL as a consequence of other genetic or epigenetic mechanisms. For example, interstitial genomic deletions also result in deregulated CRLF2 expression, whereas EPOR expression is deregulated as a consequence of the ETV6-RUNX1 fusion. The possible clinical importance of many of the various IGH translocations in BCP-ALL remains to be determined from prospective studies, but CRLF2 expression is associated with a poor prognosis. Despite their rarity, IGH chromosomal translocations in BCP-ALL therefore define not only new mechanisms of B-cell transformation but also clinically important subgroups of disease and suggest new targeted therapeutic approaches.

scholarly journals Rearrangement of immunoglobulin heavy chain genes in T cell acute lymphoblastic leukemia

Blood ◽  
1985 ◽  
Vol 65 (3) ◽  
pp. 725-729
Author(s):  
GR Kitchingman ◽  
U Rovigatti ◽  
AM Mauer ◽  
S Melvin ◽  
SB Murphy ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Heavy Chain ◽  
Germ Line ◽  
Lymphoblastic Leukemia ◽  
Immunoglobulin Heavy Chain ◽  
Chain Gene ◽  
Heavy Chain Gene ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Immunoglobulin Heavy Chain Genes

We studied the arrangement of the immunoglobulin heavy chain genes by Southern blot analysis of DNA freshly obtained from marrow blast cells of 14 children with T cell acute lymphoblastic leukemia (T-ALL) using probes to the C mu and JH gene segments: At least one of the C mu-gene alleles was rearranged in three cases. In two of these, one C mu gene had the germ-line configuration and one was rearranged, whereas both alleles were rearranged in the third case. In one case, a rearranged heavy chain gene hybridized to the C mu-region probe, but not to the JH probe, indicating that the entire JH region had been deleted. These results demonstrate that immunoglobulin heavy chain gene rearrangements are not restricted to B lineage lymphoproliferative diseases in humans.

scholarly journals Clonal, nonconstitutional rearrangements of the MLL gene in infant twins with acute lymphoblastic leukemia: in utero chromosome rearrangement of 11q23

Blood ◽  
1994 ◽  
Vol 83 (3) ◽  
pp. 641-644 ◽  
Author(s):  
HJ Gill Super ◽  
PG Rothberg ◽  
H Kobayashi ◽  
AI Freeman ◽  
MO Diaz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chromosome Rearrangement ◽  
In Utero ◽  
The Other ◽  
Chromosome Band ◽  
Cell Precursor ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Mll Gene

Abstract Rearrangements of chromosome band 11q23 are common in infant leukemias, comprising more than 70% of the observed chromosome abnormalities in children less than 1 year of age. The MLL gene, which is located at the 11q23 breakpoint in infant, childhood, and adult acute leukemias, has been cloned and has homology to the Drosophila trithorax gene. The breakpoints in MLL are restricted to an 8.3-kilobase pair (kb) region of the gene that is involved in translocations with as many as 29 other chromosomal regions in a number of phenotypically distinct acute leukemias. We have detected an identical, clonal, nonconstitutional rearrangement of the MLL gene in peripheral blood cells from a pair of female infants twins with acute lymphoblastic leukemia (ALL) and a t(11;19)(q23;p13.3). The detection of nonidentical IGH rearrangements suggests that the MLL rearrangement took place in a B-cell precursor or hematopoietic stem cell in one twin which was transferred in utero to the other fetus resulting in ALL with an identical aneuploid karyotype in both infants. We speculate that the other MLL-related infant leukemias may also develop in utero, and that the rearrangements may occur consistently in stem cells or early precursor cells, accounting for the frequency of mixed-lineage leukemia in infants.

scholarly journals Massive evolution of the immunoglobulin heavy chain locus in children with B precursor acute lymphoblastic leukemia

Blood ◽  
2012 ◽  
Vol 120 (22) ◽  
pp. 4407-4417 ◽  
Author(s):  
Charles Gawad ◽  
Francois Pepin ◽  
Victoria E. H. Carlton ◽  
Mark Klinger ◽  
Aaron C. Logan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Immunoglobulin Heavy Chain ◽  
Igh Locus ◽  
Precursor B Cells

Abstract The ability to distinguish clonal B-cell populations based on the sequence of their rearranged immunoglobulin heavy chain (IgH) locus is an important tool for diagnosing B-cell neoplasms and monitoring treatment response. Leukemic precursor B cells may continue to undergo recombination of the IgH gene after malignant transformation; however, the magnitude of evolution at the IgH locus is currently unknown. We used next-generation sequencing to characterize the repertoire of IgH sequences in diagnostic samples of 51 children with B precursor acute lymphoblastic leukemia (B-ALL). We identified clonal IgH rearrangements in 43 of 51 (84%) cases and found that the number of evolved IgH sequences per patient ranged dramatically from 0 to 4024. We demonstrate that the evolved IgH sequences are not the result of amplification artifacts and are unique to leukemic precursor B cells. In addition, the evolution often follows an allelic exclusion pattern, where only 1 of 2 rearranged IgH loci exhibit ongoing recombination. Thus, precursor B-cell leukemias maintain evolution at the IgH locus at levels that were previously underappreciated. This finding sheds light on the mechanisms associated with leukemic clonal evolution and may fundamentally change approaches for monitoring minimal residual disease burden.

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