Presence of somatic hypermutation and activation‐induced cytidine deaminase in acute lymphoblastic leukemia L2 with t(14;18)(q32;q21)

Hardianti, Mardiah Suci; Tatsumi, E; Syampurnawati, Meilani; Furuta, Kaho; Suzuki, Aya; Saigo, Katsuyasu; Takenokuchi, Mariko; Kumagai, Shunichi; Matsuo, Yoshinobu; Takeuchi, Makoto

doi:10.1111/j.1600-0609.2004.00338.x

Cited by 11 publications

(8 citation statements)

References 65 publications

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“…Despite the fact that adenosine-induced deaminase (AID) expression is detected only in some B-ALLs, 39, 40, 41, 42 the accumulation of low-level AID- or non-AID-mediated BCR mutations can result in clonal diversification. 43 Indeed, the mutations within these clusters are enriched within the CDR1-3 regions compared with FWR1-3 regions (Supplementary Figure S4) and in AID mutational motifs (Supplementary Table S10), suggestive of AID activity.…”

Section: Resultsmentioning

confidence: 99%

Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse

et al. 2016

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The strongest predictor of relapse in B-cell acute lymphoblastic leukemia (B-ALL) is the level of persistence of tumor cells after initial therapy. The high mutation rate of the B-cell receptor (BCR) locus allows high-resolution tracking of the architecture, evolution and clonal dynamics of B-ALL. Using longitudinal BCR repertoire sequencing, we find that the BCR undergoes an unexpectedly high level of clonal diversification in B-ALL cells through both somatic hypermutation and secondary rearrangements, which can be used for tracking the subclonal composition of the disease and detect minimal residual disease with unprecedented sensitivity. We go on to investigate clonal dynamics of B-ALL using BCR phylogenetic analyses of paired diagnosis-relapse samples and find that large numbers of small leukemic subclones present at diagnosis re-emerge at relapse alongside a dominant clone. Our findings suggest that in all informative relapsed patients, the survival of large numbers of clonogenic cells beyond initial chemotherapy is a surrogate for inherent partial chemoresistance or inadequate therapy, providing an increased opportunity for subsequent emergence of fully resistant clones. These results frame early cytoreduction as an important determinant of long-term outcome.

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Section: Resultsmentioning

confidence: 99%

Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse

et al. 2016

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“…Burkitt-like lymphoma cells developing in cmyc knockin mice express bcl6 but do not show SHM in the V regions, which indicates that deregulated expression of cmyc induces expression of bcl6 in cells negative for Ig SHM (38). Most importantly, AID can be expressed even in Ig SHM-negative B lymphomas, regardless of whether they derive from GC or non-GC cells (10,(12)(13)(14)(15)(16)39). (2)(3)(4)40).…”

Section: Resultsmentioning

confidence: 99%

“…However, more recent analyses have extended AID expression to other types of human B cell lymphoma, including chronic lymphocytic leukemia, Hodgkin's lymphoma, mantle cell lymphoma, mucosa-associated lymphoid tissue lymphoma, mediastinal B cell lymphoma, hairy cell leukemia, and acute lymphocytic leukemia (12)(13)(14)(15)(16). The results of these studies suggest that AID may be involved in the pathogenesis of human B cell malignancy, including not only GC-derived B cell lymphoma but also almost all other types of human B cell lymphoma.…”

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confidence: 99%

Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice

Kotani¹,

Kakazu

Tsuruyama

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Activation-induced cytidine deaminase (AID), which is essential to both class switch recombination and somatic hypermutation of the Ig gene, is expressed in many types of human B cell lymphoma/ leukemia. AID is a potent mutator because it is involved in DNA breakage not only of Ig but also of other genes, including protooncogenes. Recent studies suggest that AID is required for chromosomal translocation involving cmyc and Ig loci. However, it is unclear whether AID plays other roles in tumorigenesis. We examined the effect of AID deficiency on the generation of surface Ig-positive B cell lymphomas in Emu-cmyc transgenic mice. Almost all lymphomas that developed in AID-deficient transgenic mice were pre-B cell lymphomas, whereas control transgenic mice had predominantly B cell lymphomas, indicating that AID is required for development of B but not pre-B cell lymphomas from cmyc overexpressing tumor progenitors. Thus, AID may play multiple roles in B cell lymphomagenesis.somatic hypermutation ͉ Pim1 ͉ secondary hit ͉ clonal expansion S omatic hypermutation (SHM) originally was considered to take place specifically in the IgV genes (1). Subsequently, several genes other than those encoding Igs were shown to be targets of SHM in activated B cells and human B cell lymphomas. Such target genes include MYC, IG alpha, PAX5, BCL6, and PIM1 (2-4). Activation-induced cytidine deaminase (AID) has been shown to be essential for SHM, gene conversion, and class switch recombination (CSR), three types of genetic alteration induced by antigen stimulation of B lymphocytes (5-9).Original studies on human lymphomas indicated that AID is expressed in B cell lymphomas of germinal center (GC) origin, such as diffuse large B cell lymphoma, Burkitt's lymphoma, and follicular lymphoma, where AID is expressed physiologically (3, 10, 11). However, more recent analyses have extended AID expression to other types of human B cell lymphoma, including chronic lymphocytic leukemia, Hodgkin's lymphoma, mantle cell lymphoma, mucosa-associated lymphoid tissue lymphoma, mediastinal B cell lymphoma, hairy cell leukemia, and acute lymphocytic leukemia (12-16). The results of these studies suggest that AID may be involved in the pathogenesis of human B cell malignancy, including not only GC-derived B cell lymphoma but also almost all other types of human B cell lymphoma.Studies on AID transgenic (Tg) animals have revealed that all individual mice develop T cell lymphomas in which genes for non-Igs such as T cell receptor (tcr), cmyc, pim1, cd4, and cd5 accumulate massive mutations in the region 3Ј proximal to each promoter (17, 18). The AID Tg mice also develop B cell lymphoma, albeit much less frequently (I-m.O. and T.H., unpublished data). Studies also report AID to be essential for the mouse chromosomal translocation T(12;15), which corresponds to the human chromosomal translocation t(8;14), the hallmark of endemic Burkitt's lymphoma, in IL-6 Tg mice (19,20). However, these animals did not develop plasmacytoma; instead, they developed polyclonal ade...

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“…48,100,101 Intriguingly, at least some of these cases do not really represent a neoplasm of precursor B cells but B cells that may have reexpressed TdT, because they have accumulated somatic hypermutations, a hallmark of GC B cells. 102,103 Whatever the nature of these exceptional cases may be, many DH lymphoblastic cases in the Mitelman database 8 are incompletely documented without data on expression of TdT or CD34.…”

Section: Classificationmentioning

confidence: 99%

Double-hit B-cell lymphomas

Aukema

Siebert

Schuuring

et al. 2011

Blood

609

579

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Presence of somatic hypermutation and activation‐induced cytidine deaminase in acute lymphoblastic leukemia L2 with t(14;18)(q32;q21)

Cited by 11 publications

References 65 publications

Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse

Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse

Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice

Double-hit B-cell lymphomas

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