New biological and genetic classification and therapeutically relevant categories in childhood B-cell precursor acute lymphoblastic leukemia

Starý, Jan; Zuna, Jan; Žaliová, Markéta

doi:10.12688/f1000research.16074.1

Cited by 12 publications

(15 citation statements)

References 92 publications

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“…We observed second lesions affecting B-cell development's essential transcription factors, such as the dominant-negative IKZF1 isoforms or P2RY8-CRLF2 fusion. Finally, CRLF2 gene alterations or Ras pathway activation were detected as a third class of cooperating lesions to fully transform leukemia cells and affecting functions such as cytokine receptors and associated kinases [1,27,56]. Thus, we propose for our patients this multistep model of B-ALL pathogenesis following the findings previously reported in cell lines and mice models [1,40] (Figure 3).…”

supporting

confidence: 61%

“…As mentioned above, CRLF2 rearrangements, concurrent with other recurrent gene fusions, have been rarely described. It is possible to identify recurrent genetic fusions in combination, either in the same cell or in separate cells of the same patient [14,18,27]. These observations prompted us to describe a group of Mexican children with B-ALL and recurrent gene fusions, searching for CRLF2 rearrangements and overexpression, dominant-negative IKZF1 isoforms (Ik6, Ik8, and IKZF1a), and surrogate markers for Jak2, ABL, and Ras signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

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CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

Lorenzana

León

et al. 2021

The Journal of Pathology CR

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The gene fusions BCR‐ABL1, TCF3‐PBX1, and ETV6‐RUNX1 are recurrent in B‐cell acute lymphoblastic leukemia (B‐ALL) and are found with low frequency in coexistence with CRLF2 (cytokine receptor‐like factor 2) rearrangements and overexpression. There is limited information regarding the CRLF2 abnormalities and dominant‐negative IKZF1 isoforms associated with surrogate markers of Jak2, ABL, and Ras signaling pathways. To assess this, we evaluated 24 Mexican children with B‐ALL positive for recurrent gene fusions at diagnosis. We found CRLF2 rearrangements and/or overexpression, dominant‐negative IKZF1 isoforms, and surrogate phosphorylated markers of signaling pathways coexisting with recurrent gene fusions. All the BCR‐ABL1 patients expressed CRLF2 and were positive for pCrkl (ABL); most of them were also positive for pStat5 (Jak2/Stat5) and negative for pErk (Ras). TCF3‐PBX1 patients with CRLF2 abnormalities were positive for pStat5, most of them were also positive for pCrkl, and two patients were also positive for pErk. One patient with ETV6‐RUNX1 and intracellular CRLF2 protein expressed pCrkl. In some cases, the activated signaling pathways were reverted in vitro by specific inhibitors. We further analyzed a TCF3‐PBX1 patient at relapse, identifying a clone with the recurrent gene fusion, P2RY8‐CRLF2, rearrangement, and phosphorylation of the three surrogate markers that we studied. These results agree with the previous reports regarding resistance to treatment observed in patients with recurrent gene fusions and coexisting CRLF2 gene abnormalities. A marker phosphorylation signature was identified in BCR‐ABL1 and TCF3‐PBX1 patients. To obtain useful information for the assessment of treatment in B‐ALL patients with recurrent gene fusions, we suggest that they should be evaluated at diagnosis for CRLF2 gene abnormalities and dominant‐negative IKZF1 isoforms, in addition to the analyses of activation and inhibition of signaling pathways.

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supporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

Lorenzana

León

et al. 2021

The Journal of Pathology CR

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“…Acute lymphoblastic leukemia (ALL), the most common childhood cancer manifests as a clinically and genetically heterogenous malignancy. Both B-cell and T-cell ALL are primarily initiated by recurrent chromosomal translocations and driven by accumulation of distinct constellations of gross and sub-microscopic somatic genetic alterations including copy number alterations (CNAs), aneuploidy, structural variants, and DNA sequence mutations (1–4). Several of these lesions are important determinants of the risk of treatment failure and disease relapse but a universal agreement for inclusion of these genetic alterations in clinical risk stratification is still lacking.…”

Section: Introductionmentioning

confidence: 99%

Rapid Identification of Key Copy Number Alterations in B- and T-Cell Acute Lymphoblastic Leukemia by Digital Multiplex Ligation-Dependent Probe Amplification

et al. 2019

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Recurrent clonal genetic alterations are the hallmark of Acute Lymphoblastic Leukemia (ALL) and govern the risk stratification, response to treatment and clinical outcome. In this retrospective study conducted on ALL patient samples, the purpose was to estimate the copy number alterations (CNAs) in ALL by digitalMLPA (dMLPA), validation of the dMLPA data by conventional MLPA and RT-PCR, and correlation of CNAs with Minimal Residual Disease (MRD) status. The ALL patient samples (n = 151; B-ALL, n = 124 cases and T-ALL, n = 27 cases) were assessed for CNAs by dMLPA for detection of sub-microscopic CNAs and ploidy status. This assay allowed detection of ploidy changes and CNAs by multiplexing of karyotyping probes and probes covering 54 key gene targets implicated in ALL. Using the dMLPA assay, CNAs were detected in ~89% (n = 131) of the cases with 66% of the cases harboring ≥3 CNAs. Deletions in CDKN2A/B, IKZF1, and PAX5 genes were detectable in a quarter of these cases. Heterozygous and homozygous gene deletions, and duplications were observed in genes involved in cell cycle control, tumor suppression, lineage differentiation, lymphoid signaling, and transcriptional regulators with implications in treatment response and survival outcome. Distinct CNAs profiles were evident in B-ALL and T-ALL cases. Additionally, the dMLPA assay could reliably identify ploidy status and copy number-based gene fusions (SIL-TAL1, NUP214-ABL, EBF1-PDGFRB). Cases of B-ALL with no detectable recurrent genetic abnormalities could potentially be risk stratified based on the CNA profile. In addition to the commonly used gene deletions for risk assessment (IKZF1, EBF1, CDKN2A/B), we identified a broader spectrum of gene alterations (gains of- RUNX1, LEF1, NR3C2, PAR1, PHF6; deletions of- NF1, SUZ12, MTAP) that significantly correlated with the status of MRD clearance. The CNAs detected by dMLPA were validated by conventional MLPA and showed high concordance (r = 0.99). Our results demonstrated dMLPA to be a robust and reliable alternative for rapid detection of key CNAs in newly diagnosed ALL patients. Integration of ploidy status and CNAs detected by dMLPA with cytogenetic and clinical risk factors holds great potential in further refinement of patient risk stratification and response to treatment in ALL.

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“…Genetic abnormalities detected by standard cytogenetic (karyotyping, FISH) and molecular (PCR) methods divide B-ALL into well-established genetic subtypes. This genetic classification is essential in prediction of prognosis and thus used for the risk stratification for therapy [10].…”

Section: Discussionmentioning

confidence: 99%

Clinical impact of genomic analysis in children with B-acute lymphoblastic leukemia: A pilot study in Slovakia

Vaska

Makohusová

Plevová

et al. 2019

neo

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Acute lymphoblastic leukemia (ALL) belongs to a genetically heterogeneous disease associated with a wide range of chromosomal and molecular changes. Determining these changes at the time of diagnosis can help the therapeutic decision, and contributes to the prediction of patients' clinical outcomes. A part of BALL (B-other) lacks cytogenetic abnormalities with clinical relevance for prognosis. Our first goal was to retrospectively review genetic results of patients from 2013-2017 and identify number of Bother patients in Slovak population. The second goal was to implement single nucleotide polymorphism (SNP) array analysis to improve the diagnosis and risk stratification. In this study we reviewed 133 BALL patients. We found that nearly 40% of them (52 cases) belonged to the Bother ALL group. Eighteen Bother ALL patients were subjected to the analysis using SNP-array. Overall, we identified 126 cytogenomic changes and in 4 patients the SNP array revealed clinically relevant markers of adverse prognosis and high relapse risk. Integrating identified genetic changes into clinical practice can bring improvement of prognosis assessment for children with ALL in Slovakia.

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New biological and genetic classification and therapeutically relevant categories in childhood B-cell precursor acute lymphoblastic leukemia

Cited by 12 publications

References 92 publications

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

Rapid Identification of Key Copy Number Alterations in B- and T-Cell Acute Lymphoblastic Leukemia by Digital Multiplex Ligation-Dependent Probe Amplification

Clinical impact of genomic analysis in children with B-acute lymphoblastic leukemia: A pilot study in Slovakia

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