scholarly journals Disseminated Intravascular Coagulation Associated with Large Deletion of Immunoglobulin Heavy Chain

2021 ◽  
Author(s):  
Abbas Khalili ◽  
Amir Hosein Yadegari ◽  
Samaneh Delavari ◽  
Reza Yazdani ◽  
Hassan Abolhassani
Keyword(s):  
Heavy Chain ◽  
Immunoglobulin Heavy Chain ◽  
Genetic Alterations ◽  
Large Deletion ◽  
Disseminated Intravascular Coagulopathy ◽  
Large Deletions ◽  
Igh Locus ◽  
Intravascular Coagulopathy ◽  
The Common ◽  
Autosomal Recessive Agammaglobulinemia

Although the majority of monogenic defects underlying primary immunodeficiency are microlesions, large lesions like large deletions are rare and constitute less than 10% of these patients. The immunoglobulin heavy chain (IGH) locus is one of the common regions for such genetic alterations. This study describes a rare case of autosomal recessive agammaglobulinemia with a homozygous large deletion in chromosome 14q32.33 (106067756-106237742) immunoglobulin heavy chain clusters with an unusual and severe skin infection and disseminated intravascular coagulopathy.

Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis

Blood ◽  
2001 ◽  
Vol 98 (7) ◽  
pp. 2266-2268 ◽  
Author(s):  
Suzanne R. Hayman ◽  
Richard J. Bailey ◽  
Syed M. Jalal ◽  
Gregory J. Ahmann ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Molecular Basis ◽  
Monoclonal Gammopathy ◽  
Immunoglobulin Heavy Chain ◽  
Systemic Amyloidosis ◽  
Igh Locus ◽  
Genetic Events ◽  
14Q32 Translocation ◽  
Undetermined Significance

Primary systemic amyloidosis (AL) is a plasma cell (PC) dyscrasia with clinical similarities to multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS), but its molecular basis is poorly understood. Translocations at the immunoglobulin heavy-chain (IgH) locus, 14q32, are likely early genetic events in both MM and MGUS and involve several nonrandom, recurrent, partner chromosomes such as 11q13, 16q23, and 4p16.3. Given the similarities between MM, MGUS, and AL, bone marrow clonal PCs were evaluated in 29 patients with AL using interphase fluorescence in situ hybridization (FISH) combined with immunofluorescence detection of the cytoplasmic light-chain (cIg-FISH) for the presence of 14q32 translocations and the t(11;14)(q13;q32). Of 29 patients studied, 21 (72.4%) showed results compatible with the presence of a 14q32 translocation, and 16 (76.2%) of those had translocation (11;14)(q13;q32) for an overall prevalence of the abnormality of 55%. IgH translocations are common in AL, especially the t(11;14)(q13;q32).

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.

scholarly journals Sites That Direct Nuclear Compartmentalization Are near the 5′ End of the Mouse Immunoglobulin Heavy-Chain Locus

2005 ◽  
Vol 25 (14) ◽  
pp. 6021-6030 ◽  
Author(s):  
Qiaoxin Yang ◽  
Roy Riblet ◽  
Carl L. Schildkraut
Keyword(s):  
Heavy Chain ◽  
Nuclear Periphery ◽  
Large Change ◽  
Immunoglobulin Heavy Chain ◽  
Gene Region ◽  
Igh Locus ◽  
Mouse Immunoglobulin ◽  
Vh Gene ◽  
Vh Genes ◽  
Nuclear Compartmentalization

ABSTRACT VDJ rearrangement in the mouse immunoglobulin heavy chain (Igh) locus involves a combination of events, including a large change in its nuclear compartmentalization. Prior to rearrangement, Igh moves from its default peripheral location near the nuclear envelope to an interior compartment, and after rearrangement it returns to the periphery. To identify any sites in Igh responsible for its association with the periphery, we systematically analyzed the nuclear positions of the Igh locus in mouse non-B- and B-cell lines and, importantly, in primary splenic lipopolysaccharide-stimulated B cells and plasmablasts. We found that a broad ∼1-Mb region in the 5′ half of the variable-gene region heavy-chain (Vh) locus regularly colocalizes with the nuclear lamina. The 3′ half of the Vh gene region is less frequently colocalized with the periphery, while sequences flanking the Vh gene region are infrequently so. Importantly, in plasmacytomas, VDJ rearrangements that delete most of the Vh locus, including part of the 5′ half of the Vh gene region, result in loss of peripheral compartmentalization, while deletion of only the proximal half of the Vh gene region does not. In addition, when Igh-Myc translocations move the Vh genes to a new chromosome, the distal Vh gene region is still associated with the nuclear periphery. Thus, the Igh region that interacts with the nuclear periphery is localized but is likely comprised of multiple sites that are distributed over ∼1 Mb in the 5′ half of the Vh gene region. This 5′ Vh gene region that produces peripheral compartmentalization is the same region that is distinguished by requirements for interleukin-7, Pax5, and Ezh2 for rearrangement of the Vh genes.

Oncogenic role of Pax5 in the T-lymphoid lineage upon ectopic expression from the immunoglobulin heavy-chain locus

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 281-289 ◽  
Author(s):  
Abdallah Souabni ◽  
Wolfram Jochum ◽  
Meinrad Busslinger
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Ectopic Expression ◽  
Immunoglobulin Heavy Chain ◽  
Lymphoid Lineage ◽  
Igh Locus ◽  
T Cell Lymphomas ◽  
Cell Gene Expression

Abstract Four of 9 PAX transcription factor genes have been associated with chromosomal translocations in human tumors, although their oncogenic potential has not yet been demonstrated in transgenic mouse models. The B-lymphoidPAX5 gene participates in the generation of the t(9;14)(p13;q32) translocation in germinal center B cells, which leads to deregulated PAX5 expression under the control of the immunoglobulin heavy-chain (IgH) locus in a subset of B-cell non-Hodgkin lymphomas. Here we reconstructed a human t(9;14) translocation in a knock-in mouse by inserting a PAX5 minigene into the IgH locus. The IgHP5ki allele, which corresponds to a germline rather than somatic mutation, is activated in multipotent hematopoietic progenitors and is subsequently expressed in dendritic cells (DCs) and in natural killer (NK), T, and B cells. Ectopic Pax5 expression interferes with normal T-cell development and causes immature T-lymphoblastic lymphomas in IgHP5ki/+ and IgHP5ki/P5ki mice. Aggressive T-cell lymphomas develop even faster in IkPax5/+ mice expressing Pax5 from the Ikaros locus. Pax5 expression in thymocytes activates B-cell–specific genes and represses T-lymphoid genes, suggesting that Pax5 contributes to lymphomagenesis by deregulating the T-cell gene-expression program. These data identify Pax5 as a potent oncogene and demonstrate that the T-lymphoid lineage is particularly sensitive to the oncogenic action of Pax5.

scholarly journals Regulation of the replication of the murine immunoglobulin heavy chain gene locus: evaluation of the role of the 3' regulatory region.

1997 ◽  
Vol 17 (10) ◽  
pp. 6167-6174 ◽  
Author(s):  
J S Michaelson ◽  
O Ermakova ◽  
B K Birshtein ◽  
N Ashouian ◽  
C Chevillard ◽  
...  
Keyword(s):  
Dna Replication ◽  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Heavy Chain ◽  
Regulatory Region ◽  
Replication Timing ◽  
Immunoglobulin Heavy Chain ◽  
Igh Locus ◽  
Early Replication

DNA replication in mammalian cells is a precisely controlled physical and temporal process, likely involving cis-acting elements that control the region(s) from which replication initiates. In B cells, previous studies showed replication timing to be early throughout the immunoglobulin heavy chain (Igh) locus. The implication from replication timing studies in the B-cell line MPC11 was that early replication of the Igh locus was regulated by sequences downstream of the C alpha gene. A potential candidate for these replication control sequences was the 3' regulatory region of the Igh locus. Our results demonstrate, however, that the Igh locus maintains early replication in a B-cell line in which the 3' regulatory region has been deleted from one allele, thus indicating that replication timing of the locus is independent of this region. In non-B cells (murine erythroleukemia cells [MEL]), previous studies of segments within the mouse Igh locus demonstrated that DNA replication likely initiated downstream of the Igh gene cluster. Here we use recently cloned DNA to demonstrate that segments located sequentially downstream of the Igh 3' regulatory region continue to replicate progressively earlier in S phase in MEL. Furthermore, analysis by two-dimensional gel electrophoresis indicates that replication forks proceed exclusively in the 3'-to-5' direction through the region 3' of the Igh locus. Extrapolation from these data predicts that initiation of DNA replication occurs in MEL at one or more sites within a 90-kb interval located between 40 and 130 kb downstream of the 3' regulatory region.

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