Intragenic amplification of PAX5: a novel subgroup in B-cell precursor acute lymphoblastic leukemia?

Schwab, Claire; Nebral, Karin; Chilton, Lucy; Leschi, Cristina; Waanders, Esmé; Boer, Judith M.; Žaliová, Markéta; Sutton, Rosemary; Öfverholm, Ingegerd Ivanov; Ohki, Kentaro; Yamashita, Yuka; Groeneveld-Krentz, Stefanie; Froňková, Eva; Bâkkus, Marleen; Tchinda, Joëlle; Barbosa, Thayana da Conceição; Fazio, Grazia; Młynarski, Wojciech; Pastorczak, Agata; Cazzaniga, Giovanni; Pombo‐de‐Oliveira, Maria S.; Trka, Jan; Kirschner-Schwabe, Renate; Imamura, Toshihiko; Barbany, Gisela; Stanulla, Martin; Attarbaschi, Andishe; Panzer‐Grümayer, Renate; Kuiper, Roland P.; Boer, Monique L. den; Cavé, Hélène; Moorman, Anthony V.; Harrison, Christine J.; Strehl, Sabine

doi:10.1182/bloodadvances.2017006734

Cited by 30 publications

(41 citation statements)

References 24 publications

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“…12,13 PAX5 is also a haploinsufficient tumor suppressor gene in BCP-ALL 14,15 that is targeted by various deletions and mutations in ;30% of BCP-ALL. 4,16,17 Deletions and mutations of PAX5 have been considered so far as secondary oncogenic events because they were found in various BCP-ALL subtypes and possibly in minor subclones. However, we did not identify PAX5 P80R mutation in any case from other clusters nor in association with any classifying alteration, suggesting that this specific PAX5 mutation may define a distinct BCP-ALL subtype.…”

mentioning

confidence: 99%

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

Passet

Boissel

Sigaux

et al. 2019

Blood

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confidence: 99%

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

Passet

Boissel

Sigaux

et al. 2019

Blood

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“…Two B-ALL subtypes have distinct alterations of the lymphoid transcription factor PAX5. 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.…”

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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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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“…Similarly, CRLF2 rearrangement ( CRLF2 r) that is sometimes used to define the subset of patients within B-other ALL 45 is frequently a secondary aberration 46 and also occurs across several BCP-ALL subtypes ( BCR-ABL1 -positive ALL, BCR-ABL1 -like ALL, and hyperdiploid and hypodiploid ALL) 11 , 41 , 47 , 48 . Nevertheless, identification of these aberrations is clinically relevant, as some of them were proven to have unfavorable prognostic impact and thus influence risk stratification and therapy (for example, iAMP21 49 , 50 and TCF3–HLF 51 ) whereas in others the suggested prognostic impact needs further validation (for example, PAX5 amp 52 ). Importantly, various aberrations may qualify patients for a targeted therapy (for example, CRLF2 r) as further discussed below.…”

Section: New Bcp-all Subtypesmentioning

confidence: 99%

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

2018

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Traditionally, genetic abnormalities detected by conventional karyotyping, fluorescence in situ hybridization, and polymerase chain reaction divided childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) into well-established genetic subtypes. This genetic classification has been prognostically relevant and thus used for the risk stratification of therapy. Recently, the introduction of genome-wide approaches, including massive parallel sequencing methods (whole-genome, -exome, and -transcriptome sequencing), enabled extensive genomic studies which, together with gene expression profiling, largely expanded our understanding of leukemia pathogenesis and its heterogeneity. Novel BCP-ALL subtypes have been described. Exact identification of recurrent genetic alterations and their combinations facilitates more precise risk stratification of patients. Discovery of targetable lesions in subsets of patients enables the introduction of new treatment modalities into clinical practice and stimulates the transfer of modern methods from research laboratories to routine practice.

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Intragenic amplification of PAX5: a novel subgroup in B-cell precursor acute lymphoblastic leukemia?

Abstract: Key Points Intragenic PAX5 amplification defines a novel, relapse-prone subtype of B-cell precursor acute lymphoblastic leukemia with a poor outcome.

Cited by 30 publications

References 24 publications

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

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

Pediatric acute lymphoblastic leukemia

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

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