Immunoglobulin Gene Sequence as an Inherited and Acquired Risk Factor for Chronic Lymphocytic Leukemia

Datta, Moumita; Jumaa, Hassan

doi:10.3390/cancers14133045

Cited by 4 publications

(3 citation statements)

References 75 publications

(148 reference statements)

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“…Though this classification is almost universal, some M-CLL cases were found to be more aggressive than expected, presenting a percentage of “borderline” mutations (97–97.9% IGHV identity) and, therefore, are intermediate between U-CLL and M-CLL. 9 M-CLL is associated with better clinical outcomes than U-CLL. This has been confirmed by numerous retrospective studies, observational studies from real life, clinical trials, and meta-analysis.…”

Section: Introductionmentioning

confidence: 94%

Association of Cytogenetics Aberrations and IGHV Mutations with Outcome in Chronic Lymphocytic Leukemia Patients in a Real-World Clinical Setting

Muñoz-Novas,

González-Gascón-y-Marín,

Figueroa

et al. 2024

Glob Med Genet

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Immunoglobulin heavy chain variable (IGHV) region mutations, TP53 mutation, fluorescence in situ hybridization (FISH), and cytogenetic analysis are the most important prognostic biomarkers used in chronic lymphocytic leukemia (CLL) patients in our daily practice. In real-life environment, there are scarce studies that analyze the correlation of these factors with outcome, mainly referred to time to first treatment (TTFT) and overall survival (OS). This study aimed to typify IGHV mutation status, family usage, FISH aberrations, and complex karyotype (CK) and to analyze the prognostic impact in TTFT and OS in retrospective study of 375 CLL patients from a Spanish cohort. We found unmutated CLL (U-CLL) was associated with more aggressive disease, shorter TTFT (48 vs. 133 months, p < 0.0001), and shorter OS (112 vs. 246 months, p < 0.0001) than the mutated CLL. IGHV3 was the most frequently used IGHV family (46%), followed by IGHV1 (30%) and IGHV4 (16%). IGHV5-51 and IGHV1-69 subfamilies were associated with poor prognosis, while IGHV4 and IGHV2 showed the best outcomes. The prevalence of CK was 15% and was significantly associated with U-CLL. In the multivariable analysis, IGHV2 gene usage and del13q were associated with longer TTFT, while VH1-02, +12, del11q, del17p, and U-CLL with shorter TTFT. Moreover, VH1-69 usage, del11q, del17p, and U-CLL were significantly associated with shorter OS. A comprehensive analysis of genetic prognostic factors provides a more precise information on the outcome of CLL patients. In addition to FISH cytogenetic aberrations, IGHV and TP53 mutations, IGHV gene families, and CK information could help clinicians in the decision-making process.

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Section: Introductionmentioning

confidence: 94%

Association of Cytogenetics Aberrations and IGHV Mutations with Outcome in Chronic Lymphocytic Leukemia Patients in a Real-World Clinical Setting

Muñoz-Novas,

González-Gascón-y-Marín,

Figueroa

et al. 2024

Glob Med Genet

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“…CLL research mainly focuses on studying IGHV sequence structures. However, increasing evidence suggests that the Ig light chain (IGLV) sequence has effects on the clinical course and the outcome of CLL as well [reviewed in ( 40 )]. Lately, the IGLV3-21 gene was identified as a prognostic marker for CLL with a poor prognosis, independent of the corresponding heavy-chain ( 41 ).…”

Section: The Complex Role Of the Bcr Signaling In Cllmentioning

confidence: 99%

B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia

Schmid,

Hobeika

2024

Front. Oncol.

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B cell antigen receptor (BCR) signaling is a key driver of growth and survival in both normal and malignant B cells. Several lines of evidence support an important pathogenic role of the BCR in chronic lymphocytic leukemia (CLL). The significant improvement of CLL patients’ survival with the use of various BCR pathway targeting inhibitors, supports a crucial involvement of BCR signaling in the pathogenesis of CLL. Although the treatment landscape of CLL has significantly evolved in recent years, no agent has clearly demonstrated efficacy in patients with treatment-refractory CLL in the long run. To identify new drug targets and mechanisms of drug action in neoplastic B cells, a detailed understanding of the molecular mechanisms of leukemic transformation as well as CLL cell survival is required. In the last decades, studies of genetically modified CLL mouse models in line with CLL patient studies provided a variety of exciting data about BCR and BCR-associated kinases in their role in CLL pathogenesis as well as disease progression. BCR surface expression was identified as a particularly important factor regulating CLL cell survival. Also, BCR-associated kinases were shown to provide a crosstalk of the CLL cells with their tumor microenvironment, which highlights the significance of the cells’ milieu in the assessment of disease progression and treatment. In this review, we summarize the major findings of recent CLL mouse as well as patient studies in regard to the BCR signalosome and discuss its relevance in the clinics.

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“… 20 , 21 , 22 It was subsequently recognized that IGLV3-21 with a p.G110R mutation (termed “R110”), positioned at the variable joining-constant region boundary, generates an autoreactive B-cell receptor configuration and is selected in patients with CLL. 21 , 23 Remarkably, IGLV3-21 use is highly enriched in patients with the IP-CLL epitype, comprising approximately half of total light chain use. 17 A landmark study by Nadeu et al 22 showed that all IGLV3-21 alleles in patients with the IP-CLL epitype contained the R110 mutation, and that separation of patients with the IP epitype by the presence or absence of the IGLV3-21 R110 mutation revealed a similar separation of outcomes as found with poor risk (LP epitype) and favorable risk (HP epitype) groups, respectively.…”

Section: Introductionmentioning

confidence: 99%

Prediction of outcomes for high-count monoclonal B lymphocytosis using an epigenetic and immunogenetic signature

Abdelbaky,

Giacopelli,

Rabe

et al. 2024

Blood

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Monoclonal B cell lymphocytosis (MBL) progresses to chronic lymphocytic leukemia (CLL) requiring therapy at 1-5%/year. Improved prediction of progression would greatly benefit individuals with MBL. CLL patients separate into three distinct epigenetic subtypes (epitypes) with high prognostic significance, and recently the intermediate epitype has been shown to be enriched for high-risk IGLV3-21 rearrangements, impacting outcomes for these patients. Here we employed this combined strategy to generate the epigenetic and light chain immunoglobulin (ELCLV3-21) signature to classify 219 individuals with MBL. The ELCLV3-21 high-risk signature distinguished MBL individuals with a high probability of progression (39.9% and 71.1% at 5 and 10 years, respectively). ELCLV3-21 improved the accuracy of predicting time to therapy for MBL individuals compared to other established prognostic indicators, including the CLL international prognostic index (c-statistic 0.767 versus 0.668, respectively). Comparing ELCLV3-21 risk groups in MBL versus a cohort of 226 CLL patients revealed ELCLV3-21 high-risk MBL individuals had significantly shorter time to therapy (P=0.003) and reduced OS (P=0.03) compared to ELCLV3-21 low-risk CLL. These results highlight the power of the ELCLV3-21 approach to identify individuals with a higher likelihood of adverse clinical outcome and may provide a more accurate approach to classify individuals with small B-cell clones.-

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Immunoglobulin Gene Sequence as an Inherited and Acquired Risk Factor for Chronic Lymphocytic Leukemia

Cited by 4 publications

References 75 publications

Association of Cytogenetics Aberrations and IGHV Mutations with Outcome in Chronic Lymphocytic Leukemia Patients in a Real-World Clinical Setting

Association of Cytogenetics Aberrations and IGHV Mutations with Outcome in Chronic Lymphocytic Leukemia Patients in a Real-World Clinical Setting

B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia

Prediction of outcomes for high-count monoclonal B lymphocytosis using an epigenetic and immunogenetic signature

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