Presenting features of 201 children with acute lymphoblastic leukemia: Comparison according to presence or absence of ETV6/RUNX1 rearrangement

Álvarez, Yolanda; Caballı́n, Marı́a Rosa; Gaitán, Soledad; Pérez, A.; Bastida, Pilar; Ortega, Juan José López; Cervera, José; Verdeguer, Amparo; Tasso, M.; Aventı́n, Anna; Badell, Isabel; Guitart, Míriam; Melo, M.; Granada, Isabel; G, Javier; Dastugue, Nicole; Robert, Alain; Coll, Mercè Durfort i

doi:10.1016/j.cancergencyto.2007.05.012

Cited by 3 publications

(5 citation statements)

References 14 publications

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“…For example, in the third subtype, ETV6-RUNX1, the association test identifies a common region of LOH with a starting anchor SNP_A_2032866 (11.564295 Mb) and an ending anchor SNP_A_4281879 (12.971424 Mb) on 12p, where the region consists of 301 windows (max of Àlog 10 (p) is 7.873). The region contains multiple leukemia genes; for example, gene ETV6 encoding ETS family transcriptional factor [Alvarez et al, 2007] and gene CDKN1B encoding a protein from Cip/Kip family of cyclin-dependent kinase [Mullighan et al, 2008b;Sharif et al, 2005]. Both these genes can be found in Homo sapiens and Mus musculus.…”

Section: Results Loh Study Of the All Project Datamentioning

confidence: 99%

LOHAS: loss‐of‐heterozygosity analysis suite

Yang

Chang

Huggins

et al. 2011

Genetic Epidemiology

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Detection of loss of heterozygosity (LOH) plays an important role in genetic, genomic and cancer research. We develop computational methods to estimate the proportion of homozygous SNP calls, identify samples with structural alterations and/or unusual genotypic patterns, cluster samples with close LOH structures and map the genomic segments bearing LOH by analyzing data of genome-wide SNP arrays or customized SNP arrays. In addition to cancer genetics/genomics, we also apply the methods to study long contiguous stretches of homozygosity (LCSH) in general populations. The LCSH analysis aids in the identification of samples with complex LCSH patterns indicative of nonrandom mating and/or meiotic recombination cold spots, separation of samples with different genetic backgrounds and sex, and mapping of regions of LCSH. Affymetrix Human Mapping 500K Set SNP data from an acute lymphoblastic leukemia study containing 304 cancer patients and 50 normal controls and from the HapMap Project containing 30 African trios, 30 Caucasian trios and 90 independent Asian samples were analyzed. We identified common gene regions of LOH, e.g., ETV6 and CDKN1B, and identified frequent regions of LCSH, e.g., the region that encompasses the centromeric gene desert region of chromosome 16. Unsupervised analysis separated cancer subtypes and ethnic subpopulations by patterns of LOH/LCSH. Simulation studies considering LOH width, effect size and heterozygous interference fraction were performed, and the results show that the proposed LOH association test has good test power and controls type 1 error well. The developed algorithms are packaged into LOHAS written in R and R GUI.

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Section: Results Loh Study Of the All Project Datamentioning

confidence: 99%

LOHAS: loss‐of‐heterozygosity analysis suite

Yang

Chang

Huggins

et al. 2011

Genetic Epidemiology

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“…Using methods such as LOH‐PCR, fluorescence in situ hybridization (FISH) with chromosome painting, YAC/BAC probes, or microarray‐based comparative genomic hybridization (array CGH; aCGH) a number of studies have investigated copy number alterations (CNAs) of genes including TEL and AML1 as well as the presence of additional TEL/AML1 copies in initial and relapsed ALL. In a large proportion of t(12;21) positive ALL, the second non‐translocated TEL allele is deleted (1, 2, 4–6, 8, 10–12, 30, 32–48). Whether the loss of normal TEL function as a putative tumor suppressor gene alone or the presence of other chromosome anomalies have any influence on the occurrence of relapse is still not known.…”

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confidence: 99%

“…Furthermore, trisomy/polysomy 21 as well as gains of AML1 gene are frequently observed non‐random anomalies in both initial (3–5, 7, 8, 30, 33, 36, 37, 40, 43–45, 48–50) and relapsed (3, 37) TEL/AML1 positive ALL.…”

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confidence: 99%

Interphase FISH on TEL/AML1 positive acute lymphoblastic leukemia relapses – analysis of clinical relevance of additional TEL and AML1 copy number changes

Peter

Heiden

Taube

et al. 2009

European J of Haematology

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“… 24 Therefore, we evaluated MiR‐27a and 14‐3‐3θ transcript levels, by RT‐qPCR, in lymphocytes of patients with t(4;11) and of patients with t(12;21)(p13;q22) translocation, an indicator of good prognosis. 25 Notably, MiR‐27a levels were significantly lower in t(4;11) than in t(12;21) patients (Figure 1B , left). In contrast, although 14‐3‐3θ transcript levels were slightly higher in t(4;11) than in t(12;21) patients, the difference was not statistically significant (Figure 1B , right).…”

Section: Resultsmentioning

confidence: 92%

“…Low MiR‐27a expression levels correlate with poor prognosis and low relapse‐free survival in ALL patients 24 . Therefore, we evaluated MiR‐27a and 14‐3‐3θ transcript levels, by RT‐qPCR, in lymphocytes of patients with t(4;11) and of patients with t(12;21)(p13;q22) translocation, an indicator of good prognosis 25 . Notably, MiR‐27a levels were significantly lower in t(4;11) than in t(12;21) patients (Figure 1B, left).…”

Section: Resultsmentioning

confidence: 99%

MiR‐27a downregulates 14‐3‐3θ, RUNX1, AF4, and MLL‐AF4, crucial drivers of blast transformation in t(4;11) leukemia cells

Fioretti

Zanobio

Raia

et al. 2022

Cell Biochemistry & Function

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The chromosomal translocation t(4;11)(q21;q23), a hallmark of an aggressive form of acute lymphoblastic leukemia (ALL), encodes mixed‐lineage leukemia (MLL)‐AF4 oncogenic chimera that triggers aberrant transcription of genes involved in lymphocyte differentiation, including HOXA9 and MEIS1. The scaffold protein 14‐3‐3θ, which promotes the binding of MLL‐AF4 to the HOXA9 promoter, is a target of MiR‐27a, a tumor suppressor in different human leukemia cell types. We herein study the role of MiR‐27a in the pathogenesis of t(4;11) ALL. Reverse transcription quantitative PCR (qPCR) reveals that MiR‐27a and 14‐3‐3θ expression is inversely correlated in t(4;11) ALL cell lines; interestingly, MiR‐27a relative expression is significantly lower in patients affected by t(4;11) ALL than in patients affected by the less severe t(12;21) leukemia. In t(4;11) leukemia cells, ectopic expression of MiR‐27a decreases protein level of 14‐3‐3θ and of the key transcription factor RUNX1. We show for the first time that MiR‐27a also targets AF4 and MLL‐AF4; in agreement, MiR‐27a overexpression strongly reduces AF4 and MLL‐AF4 protein levels in RS4;11 cells. Consequent to AF4 and MLL‐AF4 downregulation, MiR‐27a overexpression negatively affects transcription of HOXA9 and MEIS1 in different t(4;11) leukemia cell lines. In agreement, we show through chromatin immunoprecipitation experiments that MiR‐27a overexpression impairs the binding of MLL‐AF4 to the HOXA9 promoter. Lastly, we found that MiR‐27a overexpression decreases viability, proliferation, and clonogenicity of t(4;11) cells, whereas it enhances their apoptotic rate. Overall, our study identifies the first microRNAthat strikes in one hit four crucial drivers of blast transformation in t(4;11) leukemia. Therefore, MiR‐27a emerges as a new promising therapeutic target for this aggressive and poorly curable form of leukemia.

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Presenting features of 201 children with acute lymphoblastic leukemia: Comparison according to presence or absence of ETV6/RUNX1 rearrangement

Cited by 3 publications

References 14 publications

LOHAS: loss‐of‐heterozygosity analysis suite

LOHAS: loss‐of‐heterozygosity analysis suite

Interphase FISH on TEL/AML1 positive acute lymphoblastic leukemia relapses – analysis of clinical relevance of additional TEL and AML1 copy number changes

MiR‐27a downregulates 14‐3‐3θ, RUNX1, AF4, and MLL‐AF4, crucial drivers of blast transformation in t(4;11) leukemia cells

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