Multidisciplinary diagnostics of chronic lymphocytic leukemia: European Research Initiative on CLL - ERIC recommendations

Zalcberg, Ilana; D’Andrea, Mariana Gamma; Monteiro, Lúcia Ramos; Pimenta, Glicínia; Xisto, Beth

doi:10.1016/j.htct.2019.07.006

Cited by 14 publications

(18 citation statements)

References 27 publications

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“…6 k). Several genetic alterations detected by FISH are prevalent among CLL patients, reflecting varying degrees of association with disease prognosis [ 43 ]. The presence of one or two C alleles was more common within the group of patients with chromosomal alterations determined by FISH than those with no alterations (Fig.…”

Section: Resultsmentioning

confidence: 99%

Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia

et al. 2022

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Background Chronic lymphocytic leukemia (CLL) is the most frequent, and still incurable, form of leukemia in the Western World. It is widely accepted that cancer results from an evolutionary process shaped by the acquisition of driver mutations which confer selective growth advantage to cells that harbor them. Clear examples are missense mutations in classic RAS genes (KRAS, HRAS and NRAS) that underlie the development of approximately 13% of human cancers. Although autonomous B cell antigen receptor (BCR) signaling is involved and mutations in many tumor suppressor genes and oncogenes have been identified, an oncogenic driver gene has not still been identified for CLL. Methods Conditional knock-in mice were generated to overexpress wild type RRAS2 and prove its driver role. RT-qPCR analysis of a human CLL sample cohort was carried out to measure RRAS2 transcriptional expression. Sanger DNA sequencing was used to identify a SNP in the 3’UTR region of RRAS2 in human CLL samples. RNAseq of murine CLL was carried out to identify activated pathways, molecular mechanisms and to pinpoint somatic mutations accompanying RRAS2 overexpression. Flow cytometry was used for phenotypic characterization and shRNA techniques to knockdown RRAS2 expression in human CLL. Results RRAS2 mRNA is found overexpressed in its wild type form in 82% of the human CLL samples analyzed (n = 178, mean and median = 5-fold) as well as in the explored metadata. A single nucleotide polymorphism (rs8570) in the 3’UTR of the RRAS2 mRNA has been identified in CLL patients, linking higher expression of RRAS2 with more aggressive disease. Deliberate overexpression of wild type RRAS2 in mice, but not an oncogenic Q72L mutation in the coding sequence, provokes the development of CLL. Overexpression of wild type RRAS2 in mice is accompanied by a strong convergent selection of somatic mutations in genes that have been identified in human CLL. R-RAS2 protein is physically bound to the BCR and mediates BCR signals in CLL. Conclusions The results indicate that overexpression of wild type RRAS2 is behind the development of CLL.

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Section: Resultsmentioning

confidence: 99%

Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia

et al. 2022

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“… 4 , 24 Using this approach in chronic lymphocytic leukemia, it was demonstrated that an MRD threshold of 0.01% (10 -4 ) was an independent predictor of progression-free survival in patients treated with either chemo-immunotherapy or novel agents. 33 …”

Section: Discussionmentioning

confidence: 99%

Clinical relevance of an objective flow cytometry approach based on limit of detection and limit of quantification for measurable residual disease assessment in acute myeloid leukemia. A post-hoc analysis of the GIMEMA AML1310 trial

Buccisano¹,

Palmieri

Piciocchi

et al. 2022

haematol

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Using a multiparametric flow cytometry (MFC) assay, we assessed the predictive power of a threshold calculated applying the criteria of limit of detection (LOD) and limit of quantitation (LOQ) in adult patients affected with Acute Myeloid Leukemia (AML). This was a post-hoc analysis of 261 patients enrolled in the GIMEMA AML1310 prospective trial. According to the protocol design, using the predefined MRD threshold of 0.035% bone marrow residual leukemic cell (RLC) calculated on mononuclear cells, 154 (59%) were negative (MRD

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“…Currently, the inclusion of TL evaluation in the proposed algorithm may be considered problematic as TL analysis has not yet been subjected to international standardisation. However, if a biomarker is deemed useful enough, then the requisite validation and standardisation will be performed as exemplified by the international effort to standardise IGHV mutation analysis, as well as TP53 mutations [11,12]. As part of the effort to develop a robust, reliable and accurate TL assay, suitable for clinical applications, high-throughput STELA was developed; this assay circumvents the labour intensive and technical issues of the original single molecule STELA assay and it has been already successfully employed for the evaluation of large numbers of clinical samples [13].…”

Section: To the Editormentioning

confidence: 99%

Combined analysis of IGHV mutations, telomere length and CD49d identifies long-term progression-free survivors in TP53 wild-type CLL treated with FCR-based therapies

et al. 2021

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Multidisciplinary diagnostics of chronic lymphocytic leukemia: European Research Initiative on CLL - ERIC recommendations

Cited by 14 publications

References 27 publications

Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia

Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia

Clinical relevance of an objective flow cytometry approach based on limit of detection and limit of quantification for measurable residual disease assessment in acute myeloid leukemia. A post-hoc analysis of the GIMEMA AML1310 trial

Combined analysis of IGHV mutations, telomere length and CD49d identifies long-term progression-free survivors in TP53 wild-type CLL treated with FCR-based therapies

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