PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice

Jamrog, Laura; Chemin, Guillaume; Fregona, Vincent; Coster, Lucie; Pasquet, Marlène; Oudinet, Chloé; Rouquié, Nelly; Prade, Naïs; Lagarde, Stéphanie; Cresson, Charlotte; Hébrard, Sylvie; Huu, Ngoc Sa Nguyen; Bousquet, Marina; Quelen, Cathy; Brousset, Pierre; Mancini, Stéphane; Delabesse, Éric; Khamlichi, Ahmed Amine; Gerby, Bastien; Broccardo, Cyril

doi:10.1073/pnas.1721678115

Cited by 21 publications

(46 citation statements)

References 36 publications

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“…One study hypothesized that loss of USP9X (seen in 4/17 CRLF2-rearranged cases), which encodes a deubiquitinase known to stabilize activated JAK2, may naturally buffer the toxic effect of JAK/STAT signaling hyperactivation in DS-ALL [67]. In addition, activating mutations in signaling effectors have been shown to functionally cooperate with loss of Ink4a/Arf and Pax5 alterations to drive B-cell leukemia development in vivo [75,76].…”

Section: Somatic Alterations Found In Ds-allmentioning

confidence: 99%

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

2020

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Structural and numerical alterations of chromosome 21 are extremely common in hematological malignancies. While the functional impact of chimeric transcripts from fused chromosome 21 genes such as TEL-AML1, AML1-ETO, or FUS-ERG have been extensively studied, the role of gain of chromosome 21 remains largely unknown. Gain of chromosome 21 is a frequently occurring aberration in several types of acute leukemia and can be found in up to 35% of cases. Children with Down syndrome (DS), who harbor constitutive trisomy 21, highlight the link between gain of chromosome 21 and leukemogenesis, with an increased risk of developing acute leukemia compared with other children. Clinical outcomes for DS-associated leukemia have improved over the years through the development of uniform treatment protocols facilitated by international cooperative groups. The genetic landscape has also recently been characterized, providing an insight into the molecular pathogenesis underlying DS-associated leukemia. These studies emphasize the key role of trisomy 21 in priming a developmental stage and cellular context susceptible to transformation, and have unveiled its cooperative function with additional genetic events that occur during leukemia progression. Here, using DS-leukemia as a paradigm, we aim to integrate our current understanding of the role of trisomy 21, of critical dosage-sensitive chromosome 21 genes, and of associated mechanisms underlying the development of hematological malignancies. This review will pave the way for future investigations on the broad impact of gain of chromosome 21 in hematological cancer, with a view to discovering new vulnerabilities and develop novel targeted therapies to improve long term outcomes for DS and non-DS patients.

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Section: Somatic Alterations Found In Ds-allmentioning

confidence: 99%

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

2020

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“…PAX5 is a haplotype tumor suppressor gene in human B-All, which is involved in a variety of chromosome translocation ( Jamrog et al, 2018 ). In the investigation and analysis of Bastian et al (2019) , it was found that the army of patients with BCP-ALL subgroup carried PAX5 mutation.…”

Section: Resultsmentioning

confidence: 99%

Multi-Omics Analysis of Acute Lymphoblastic Leukemia Identified the Methylation and Expression Differences Between BCP-ALL and T-ALL

Ying

et al. 2021

Front. Cell Dev. Biol.

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Acute lymphoblastic leukemia (ALL) as a common cancer is a heterogeneous disease which is mainly divided into BCP-ALL and T-ALL, accounting for 80–85% and 15–20%, respectively. There are many differences between BCP-ALL and T-ALL, including prognosis, treatment, drug screening, gene research and so on. In this study, starting with methylation and gene expression data, we analyzed the molecular differences between BCP-ALL and T-ALL and identified the multi-omics signatures using Boruta and Monte Carlo feature selection methods. There were 7 expression signature genes (CD3D, VPREB3, HLA-DRA, PAX5, BLNK, GALNT6, SLC4A8) and 168 methylation sites corresponding to 175 methylation signature genes. The overall accuracy, accuracy of BCP-ALL, accuracy of T-ALL of the RIPPER (Repeated Incremental Pruning to Produce Error Reduction) classifier using these signatures evaluated with 10-fold cross validation repeated 3 times were 0.973, 0.990, and 0.933, respectively. Two overlapped genes between 175 methylation signature genes and 7 expression signature genes were CD3D and VPREB3. The network analysis of the methylation and expression signature genes suggested that their common gene, CD3D, was not only different on both methylation and expression levels, but also played a key regulatory role as hub on the network. Our results provided insights of understanding the underlying molecular mechanisms of ALL and facilitated more precision diagnosis and treatment of ALL.

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“…Such profiling has demonstrated the accuracy of mouse models of common translocations that occur in B-ALL/LBL, such as ETV6-RUNX1 , 59 MLL-AF4 , 27 and PAX5-ELN . 24…”

Section: Discussionmentioning

confidence: 99%

Immunophenotyping of Murine Precursor B-Cell Leukemia/Lymphoma: A Comparison of Immunohistochemistry and Flow Cytometry

et al. 2019

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In humans and in mouse models, precursor B-cell lymphoblastic leukemia (B-ALL)/lymphoblastic lymphoma (B-LBL) can be classified as either the pro-B or pre-B subtype. This is based on the expression of antigens associated with the pro-B and pre-B stages of B-cell development. Antigenic markers can be detected by flow cytometry or immunohistochemistry (IHC), but no comparison of results from these techniques has been reported for murine B-ALL/LBL. In our analysis of 30 cases induced by chemical or viral mutagenesis on a WT or Pax5+/– background, 18 (60%) were diagnosed as pro-B by both flow cytometry and IHC. Discordant results were found for 12 (40%); 6 were designated pro-B by IHC and pre-B by flow cytometry and the reverse for the remaining 6 cases. Discordance occurred because different markers were used to define the pro-B–to–pre-B transition by IHC vs flow cytometry. IHC expression of cytoplasmic IgM (μIgM) defined the pre-B stage, whereas the common practice of using CD25 as a surrogate marker in flow cytometry was employed here. These results show that CD25 and μIgM are not always concurrently expressed in B-ALL/LBL, in contrast to normal B-cell development. Therefore, when subtyping B-ALL/LBL in mice, an IHC panel of B220, PAX5, TdT, c-Kit/CD117, CD43, IgM, and ΚLC should be considered. For flow cytometry, cytoplasmic IgM may be an appropriate marker in conjunction with the surface markers B220, CD19, CD43, c-Kit/CD117, BP-1, and CD25.

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PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice

Cited by 21 publications

References 36 publications

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

Multi-Omics Analysis of Acute Lymphoblastic Leukemia Identified the Methylation and Expression Differences Between BCP-ALL and T-ALL

Immunophenotyping of Murine Precursor B-Cell Leukemia/Lymphoma: A Comparison of Immunohistochemistry and Flow Cytometry

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