Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogénétique Hématologique study

Coyaud, Étienne; Struski, Stéphanie; Prade, Naïs; Familiadès, J; Eichner, Ruth; Quelen, Cathy; Bousquet, Marina; Mugneret, Francine; Talmant, Pascaline; Pagès, Marie-Pierre; Lefebvre, Catherine Lemieux; Penther, Dominique; Lippert, Éric; Nadal, Nathalie; Taviaux, Sylvie; Poppe, Bruce; Luquet, Isabelle; Baranger, Laurence; Éclache, Virginie; Radford, Isabelle; Barin, Carole; Mozziconacci, Marie‐Joëlle; Lafage‐Pochitaloff, Marina; Antoine‐Poirel, Hélène; Charrin, C; Pérot, Christine; Terré, Christine; Brousset, Pierre; Dastugue, Nicole; Broccardo, Cyril

doi:10.1182/blood-2009-07-234229

Cited by 104 publications

(111 citation statements)

References 21 publications

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“…Li et al (14) showed that miR-17∼92 targets TGFßR2 to induce cell proliferation (14). TAOK1 was found to be a fusion partner of PAX5 in B-cell acute lymphoblastic leukemia (15). Abcc3 is a member of the ABC transporter family and is involved in drug transport or redistribution of imatinib and dasatinib anticancer agents.…”

Section: Discussionmentioning

confidence: 99%

B-cell malignancies in microRNA Eμ-miR-17∼92 transgenic mice

Sandhu

Fassan

Volinia

et al. 2013

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

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miR-17∼92 is a polycistronic microRNA (miR) cluster (consisting of miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a) which frequently is overexpressed in several solid and lymphoid malignancies. Loss-and gain-of-function studies have revealed the role of miR-17∼92 in heart, lung, and B-cell development and in Mycinduced B-cell lymphomas, respectively. Recent studies indicate that overexpression of this locus leads to lymphoproliferation, but no experimental proof that dysregulation of this cluster causes B-cell lymphomas or leukemias is available. To determine whether miR-17∼92-overexpression induces lymphomagenesis/leukemogenesis, we generated a B-cell-specific transgenic mouse model with targeted overexpression of this cluster in B cells. The miR-17∼92 overexpression was driven by the Eμ-enhancer and Ig heavy-chain promoter, and a 3′ GFP tag was added to the transgene to track the miR expression. Expression analysis using Northern Blot and quantitative RT-PCR confirmed 2.5-to 25-fold overexpression of all six miRs in the transgenic mice spleens as compared with spleens from wild-type mice. Eμ-miR-17∼92 mice developed B-cell malignancy by the age of 12-18 mo with a penetrance of ∼80% (49% splenic B-cell lymphoproliferative disease, 28% lymphoma). At this stage mice exhibited severe splenomegaly with abnormal B-cell-derived white pulp expansion and enlarged lymph nodes. Interestingly, we found three classes of B-cell lymphomas/leukemias at varying grades of differentiation. These included expansion of CD19 + and CD5 + double-positive B cells similar to the aggressive form of human B-cell chronic lymphocytic leukemia, B220 + CD43 + B1-cell proliferation, and a CD19 + aggressive diffuse large B-cell lymphoma-like disease, as assessed by flow cytometry and histopathological analysis. miR-17∼92 cluster | animal model | SLC/ABC transporters M icroRNAs (miRs) are 21-to 22-nucleotide-long noncoding RNA molecules that regulate the expression of multiple cellular genes, and their dysregulation is involved in many human diseases including cancer. The MiR-17∼92 cluster frequently is up-regulated in several different malignancies including diffuse large B-cell lymphoma (DLBCL) (1) and lung cancer (2, 3). The MiR-17∼92 cluster is encoded by the chromosome 13q31 locus in humans and the 14qE4 locus in mice. This genomic region is amplified in DLBCLs and several other tumors (reviewed in ref. 4). The cluster consists of six miRs (miR-17, 18a, 19a, 20a, 19b-1, and 92a-1) and has two paralogs in the genome, miR-106a∼363 and miR-106b∼25, proposed to have arisen through series of duplication and deletion events during vertebrate evolution (5).The first suggestion for its possible role in oncogenesis came from the study in Eμ-Myc mice in which enforced expression of miR-17∼92 was shown to accelerate B-cell tumor development (6). An additional study that investigated the role of miR-17∼92 in mice by driving its overexpression under the human CD2 promoter in both B and T cells found that mice overexpressing the miR-17∼92 clust...

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Section: Discussionmentioning

confidence: 99%

B-cell malignancies in microRNA Eμ-miR-17∼92 transgenic mice

Sandhu

Fassan

Volinia

et al. 2013

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

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“…Previous studies by others and ourselves found that the PAX5 gene was rearranged to at least 20 partner genes in pediatric ALL samples. 1,[29][30][31][32][33] Each of these fusion genes retains the DNA-binding paired domain, but lacks the transcriptional activation domain of the PAX5 gene. The fusion proteins may bind to promoter regions of PAX5 target genes but probably do not have transcriptional activity, thus acting as dominant negative molecules preventing Bcell differentiation by wild-type PAX5.…”

Section: Discussionmentioning

confidence: 99%

Genomic profiling of adult acute lymphoblastic leukemia by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric acute lymphoblastic leukemia

Okamoto¹,

Ogawa²,

Nowak³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundDifferences in survival have been reported between pediatric and adult acute lymphoblastic leukemia. The inferior prognosis in adult acute lymphoblastic leukemia is not fully understood but could be attributed, in part, to differences in genomic alterations found in adult as compared to in pediatric acute lymphoblastic leukemia. Design and MethodsWe compared two different sets of high-density single nucleotide polymorphism array genotyping data from 75 new diagnostic adult and 399 previously published diagnostic pediatric acute lymphoblastic leukemia samples. The patients' samples were randomly acquired from among Caucasian and Asian populations and hybridized to either Affymetrix 50K or 250K single nucleotide polymorphism arrays. The array data were investigated with Copy Number Analysis for GeneChips (CNAG) software for allele-specific copy number analysis. ResultsThe high density single nucleotide polymorphism array analysis of 75 samples of adult acute lymphoblastic leukemia led to the identification of numerous cryptic and submicroscopic genomic lesions with a mean of 7.6 genomic alterations per sample. The patterns and frequencies of lesions detected in the adult samples largely reproduced known genomic hallmarks detected in previous single nucleotide polymorphism-array studies of pediatric acute lymphoblastic leukemia, such as common deletions of 3p14.2 (FHIT), 5q33.3 (EBF), 6q, 9p21.3 (CDKN2A/B), 9p13.2 (PAX5), 13q14.2 (RB1) and 17q11.2 (NF1). Some differences between adult and pediatric acute lymphoblastic leukemia were identified when the pediatric data set was partitioned into hyperdiploid and non-hyperdiploid cases and then compared to the nearly exclusively non-hyperdiploid adult samples. In this analysis, adult samples had a higher rate of deletions of chromosome 17p (TP53) and duplication of 17q. ConclusionsOur analysis of adult acute lymphoblastic leukemia cases led to the identification of new potential target lesions relevant for the pathogenesis of acute lymphoblastic leukemia. However, no unequivocal pattern of submicroscopic genomic alterations was found to separate adult acute lymphoblastic leukemia from pediatric acute lymphoblastic leukemia. Therefore, apart from different therapy regimen, differences of prognosis between adult and pediatric acute lymphoblastic leukemia are probably based on genetic subgroups according to cytogenetically detectable lesions but not focal genomic copy number microlesions.Key words: SNP-array; adult ALL; pediatric ALL; comparative study.Citation: Okamoto R, Ogawa S, Nowak D, Kawamata N, Akagi T, Kato M, Sanada M, Weiss T, Haferlach C, Dugas M, Ruckert C, Haferlach T, and

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“…Cytogenetic analysis of bone marrow samples was performed by standard methods and FISH as described 8 (supplemental Methods, supplemental Figure 1). …”

Section: Fishmentioning

confidence: 99%

Identification of a transforming MYB-GATA1 fusion gene in acute basophilic leukemia: a new entity in male infants

Quelen

Lippert

Struski

et al. 2011

Blood

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Acute basophilic leukemia (ABL) is a rare subtype of acute leukemia with clinical features and symptoms related to hyperhistaminemia because of excessive growth of basophils. No known recurrent cytogenetic abnormality is associated with this leukemia. Rare cases of t(X;6)(p11;q23) translocation have been described but these were sporadic. We report here 4 cases of ABL with a t(X;6)(p11;q23) translocation occurring in male infants. Because of its location on chromosome 6q23, MYB was a good candidate gene. Our molecular investigations, based on fluorescence in situ hybridization and rapid amplification of cDNA ends, revealed that the translocation generated a MYB-GATA1 fusion gene. Expression of MYB-GATA1 IntroductionAcute myeloid leukemia (AML) accounts for 15%-20% of cases of childhood leukemia. 1-2 Acute basophilic leukemia (ABL) is a rare subtype of acute leukemia. Clinical features are close to those of poorly differentiated AML with, in some cases, symptoms related to hyperhistaminemia because of excessive expansion of the basophil compartment. 3 The diagnosis of ABL is associated with detection of basophil blast cells. To date, because of the rarity of ABL cases, no recurrent cytogenetic abnormality has been described. Rare cases of t(X;6)(p11;q23) translocations have been reported but these were sporadic. [4][5] Of note, a very recent paper reported the cloning of the t(X;6)(p11;q23) in a case of acute monoblastic leukemia. 6 We report here 4 cases of ABL with a t(X;6)(p11;q23) translocation occurring in male infants. Patients P1 and P2 have been reported previously. 4 Because of its location on chromosome 6q23 and its well established involvement in oncogenesis, 7 MYB was a good candidate gene. Our molecular investigations, based on fluorescence in situ hybridization (FISH) and rapid amplification of cDNA ends (RACE), revealed that the translocation generated a MYB-GATA1 fusion gene. This chimera commits myeloid cells to the granulocyte lineage and blocks their differentiation. Methods PatientsCharacteristics of the patients fit with the diagnosis of ABL (supplemental Methods and supplemental Table 1, available on Blood Web site; see the Supplemental Materials link at the top of the online article). FISHCytogenetic analysis of bone marrow samples was performed by standard methods and FISH as described 8 (supplemental Methods, supplemental Figure 1). Cloning of MYB-GATA1MYB-GATA1 was isolated using the 5Ј/3Ј RACE Kit (Roche). Full-length MYB-GATA1 cDNA was cloned into the retroviral pMSCVIresEGFP vector (pMIE-MG; supplemental Table 2). Screening of mutationsThe mutational status of FLT3, NPM1, WT1, CEBPa, K-RAS, N-RAS, IDH1, IDH2 was investigated by high-resolution melting and multiplex PCR (supplemental Table 2). CFC assaysColony forming cell (CFC) assays were performed on mouse lineagenegative (lin Ϫ ) cells harvested from C57BL/6 mice, sorted using a Lineage Cell Depletion Kit (Miltenyi Biotec) and transduced with pMIE (control) or pMIE-MG (MYB-GATA1) retroviral vectors. Cells were seeded in triplicate...

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Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogénétique Hématologique study

Cited by 104 publications

References 21 publications

B-cell malignancies in microRNA Eμ-miR-17∼92 transgenic mice

B-cell malignancies in microRNA Eμ-miR-17∼92 transgenic mice

Genomic profiling of adult acute lymphoblastic leukemia by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric acute lymphoblastic leukemia

Identification of a transforming MYB-GATA1 fusion gene in acute basophilic leukemia: a new entity in male infants

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