PAX5 P80R mutation identifies a novel subtype of B-cell precursor acute lymphoblastic leukemia with favorable outcome

Passet, Marie; Boissel, Nicolas; Sigaux, François; Saillard, Colombe; Bargetzi, Mario; Ba, Ibrahima; Thomas, Xavier; Graux, Carlos; Chalandon, Yves; Leguay, Thibaut; Lengliné, Étienne; Konopacki, Johanna; Quentin, Samuel; Delabesse, Éric; Lafage‐Pochitaloff, Marina; Pastoret, Cédric; Grardel, Nathalie; Asnafi, Vahid; Lhéritier, Véronique; Soulier, Jean; Dombret, Hervé; Clappier, Emmanuelle

doi:10.1182/blood-2018-10-882142

Cited by 61 publications

(63 citation statements)

References 22 publications

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“…PAX5-altered (PAX5alt) B-ALL accounts for 10% of childhood B-ALL, with cases featuring diverse PAX5 alterations, including rearrangements (most commonly with ETV6 or NOL4L), sequence mutations or intragenic amplification, 54 and an intermediate prognosis. 15,47 PAX5 P80R B-ALL accounts for approximately 2% of childhood B-ALL, with cases featuring universal P80R mutation and deletion/mutation of the remaining allele, 15,47,55 mutations in Ras and JAK2 signaling genes, and an intermediate to favorable prognosis. 15,55 A single heterozygous mutation in IKZF1 (N159Y) defines a novel subtype of ALL (representing <1% of cases) with IKZF1 nuclear mislocalization, enhanced intercellular adhesion, 56 and expression of genes involved in oncogenesis (YAP1), chromatin remodeling (SALL1), and JAK-STAT signaling.…”

Section: Other Transcription Factor-driven Subtypes Of B-cell Acute Lmentioning

confidence: 99%

“…15,47 PAX5 P80R B-ALL accounts for approximately 2% of childhood B-ALL, with cases featuring universal P80R mutation and deletion/mutation of the remaining allele, 15,47,55 mutations in Ras and JAK2 signaling genes, and an intermediate to favorable prognosis. 15,55 A single heterozygous mutation in IKZF1 (N159Y) defines a novel subtype of ALL (representing <1% of cases) with IKZF1 nuclear mislocalization, enhanced intercellular adhesion, 56 and expression of genes involved in oncogenesis (YAP1), chromatin remodeling (SALL1), and JAK-STAT signaling. 15,47 The IGH-CEBPE fusion and ZEB2 H1038R mutation are common, but not universal, events in a transcriptionally distinct form of leukemia observed in approximately 1% of cases.…”

Section: Other Transcription Factor-driven Subtypes Of B-cell Acute Lmentioning

confidence: 99%

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Pediatric acute lymphoblastic leukemia

Inaba¹,

Mullighan²

2020

haematol

436

267

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The last decade has witnessed great advances in our understanding of the genetic and biological basis of childhood acute lymphoblastic leukemia (ALL), the development of experimental models to probe mechanisms and evaluate new therapies, and the development of more efficacious treatment stratification. Genomic analyses have revolutionized our understanding of the molecular taxonomy of ALL, and these advances have led the push to implement genome and transcriptome characterization in the clinical management of ALL to facilitate more accurate risk-stratification and, in some cases, targeted therapy. Although mutation- or pathway-directed targeted therapy (e.g., using tyrosine kinase inhibitors to treat Philadelphia chromosome [Ph]-positive and Phlike B-cell-ALL) is currently available for only a minority of children with ALL, many of the newly identified molecular alterations have led to the exploration of approaches targeting deregulated cell pathways. The efficacy of cellular or humoral immunotherapy has been demonstrated with the success of chimeric antigen receptor T-cell therapy and the bispecific engager blinatumomab in treating advanced disease. This review describes key advances in our understanding of the biology of ALL and optimal approaches to risk-stratification and therapy, and it suggests key areas for basic and clinical research.

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Section: Other Transcription Factor-driven Subtypes Of B-cell Acute Lmentioning

confidence: 99%

Section: Other Transcription Factor-driven Subtypes Of B-cell Acute Lmentioning

confidence: 99%

Pediatric acute lymphoblastic leukemia

Inaba¹,

Mullighan²

2020

haematol

436

267

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“…Since neither V 26 G (EBNA1 binding mutant) nor P 80 R (EBNA1 bound) were able to restore the defects in EBNA1/oriP-Luc-induced transcription levels of oriP-TRs-nLuc caused by PAX5 depletion, it implies that multiple PAX5-driven events are crucially involved in EBNA1/oriP-mediated transcription. Apart from knowing the EBNA1/PAX5mediated PPI is a basic requirement, the inability of P 80 R to restore EBNA1/oriPdependent transcription in a PAX5-depleted condition could be due to the loss of its interaction with p300 or to the partial loss of function of PAX5 on its target genes (43). Although the TRs are not essential, the PAX5-mediated recruitment of p300 and H3K4Me3 to the TRs may further enhance the EBNA1/oriP-mediated transcription via the PAX5-EBNA1-oriP axis.…”

Section: Discussionmentioning

confidence: 99%

B Cell-Specific Transcription Activator PAX5 Recruits p300 To Support EBNA1-Driven Transcription

Liu

Lee

Peng

2020

J Virol

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The binding of Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA1) to the latent replication origin (oriP) triggers multiple downstream events to support virus-induced pathogenesis and tumorigenesis. Although EBV is widely recognized as a B-lymphotropic infectious agent, little is known about how tissue-specific factors are involved in the establishment of latency. Here, we showed that EBNA1 binds B cell activator PAX5 to promote EBNA1/oriP-dependent binding and transcription. In addition to showing that short hairpin RNA (shRNA)-mediated PAX5 knockdown substantially abrogated the above EBNA1-dependent functions, two mini-EBV reporter plasmids were used to perform nonlytic nano-luciferase (nLuc) activity and chromatin immunoprecipitation (ChIP) assays to show how EBNA1 cooperates with PAX5 to activate the transcription at the oriP site. The expression plasmids of two PAX5 mutants, V26G (EBNA1 binding mutant) and P80R (which remained EBNA1 associated), were used to assess their capability to restore the defects caused by PAX5 depletion in EBNA1/oriP-mediated binding, transcription, and maintenance of the genome copy number of the mini-EBV episome reporter in BJAB cells stably expressing EBNA1 or that of the EBV genome in EBV-infected BJAB cells. Since p300 is known to be associated with PAX5, we showed that the loss of function of the P80R mutant in support of EBNA1/oriP-mediated transcription under PAX5 depletion conditions was linked to its defective binding to p300. ChIP-quantitative PCR (qPCR) confirmed that P80R indeed failed to recruit p300 to the oriP DNA. Our discovery suggests that EBV has evolved an exquisite strategy to take advantage of tissue-specific factors to enable the establishment of viral latency. IMPORTANCE Although B cells are known to be the primary target for EBV infection, there is limited knowledge regarding the mechanism that determines this preferable tissue tropism. An in-depth understanding of the potential link of tissue-specific factors with the viral genes and their functioning is key to deciphering how EBV induces persistent infection in the distinct types of host cells. In this study, a substantial protein-protein interaction mediated by the B cell-specific activator PAX5 and EBNA1 was identified as the general requirement for the binding of EBNA1 to the latent replication origin and for downstream events. Of importance, the EBNA1-PAX5-p300 network is directly linked to EBNA1-dependent transcription. These findings suggest that targeting the viral gene-associated tissue-specific factors may lead to new therapeutic strategies for EBV-associated malignancies.

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“…The second group of PAX5-driven ALL is defined by the presence of the PAX5 P80R mutation, which is homozygous in almost all cases because of deletion or frameshift mutation of the wild-type PAX5 allele, suggesting that loss of both PAX5 alleles drives the unique gene expression profile of this subtype ( Fig. 3; Li et al 2018;Gu et al 2019;Passet et al 2019). The prevalence of PAX5 P80R increases with age, accounting for almost 5% of adults.…”

Section: Pax5-driven Subtypesmentioning

confidence: 99%

“…The prevalence of PAX5 P80R increases with age, accounting for almost 5% of adults. This subtype confers an intermediate to favorable prognosis in both children and adults (Bastian et al 2019;Gu et al 2019;Passet et al 2019;Zaliova et al 2019). Cooperating lesions identified in PAX5 P80R patients include a high frequency of signaling mutations, particularly in the Ras, JAK-STAT, and other kinase signaling pathways (FLT3, PIK3CA), highlighting the potential for targeted therapies (Gu et al 2019;Passet et al 2019).…”

Section: Pax5-driven Subtypesmentioning

confidence: 99%

The Biology of B-Progenitor Acute Lymphoblastic Leukemia

Roberts

Mullighan

2019

Cold Spring Harb Perspect Med

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Genomic analyses have revolutionized our understanding of the biology of B-progenitor acute lymphoblastic leukemia (ALL). Studies of thousands of cases across the age spectrum have revised the taxonomy of BALL by identifying multiple new subgroups with diverse sequence and structural initiating events that vary substantially by age at diagnosis and prognostic significance. There is a growing appreciation of the role of inherited genetic variation in predisposition to ALL and drug responsiveness and of the nature of genetic variegation and clonal evolution that may be targeted for improved diagnostic, risk stratification, disease monitoring, and therapeutic intervention. This review provides an overview of the current state of knowledge of the genetic basis of BALL , with an emphasis on recent discoveries that have changed our approach to diagnosis and monitoring.

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PAX5 P80R mutation identifies a novel subtype of B-cell precursor acute lymphoblastic leukemia with favorable outcome

Cited by 61 publications

References 22 publications

Pediatric acute lymphoblastic leukemia

Pediatric acute lymphoblastic leukemia

B Cell-Specific Transcription Activator PAX5 Recruits p300 To Support EBNA1-Driven Transcription

The Biology of B-Progenitor Acute Lymphoblastic Leukemia

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