PAX5 biallelic genomic alterations define a novel subgroup of B-cell precursor acute lymphoblastic leukemia

Bastian, Lorenz; Schroêder, M.; Eckert, Cornelia; Schlee, Cornelia; Tanchez, Jutta Ortiz; Kämpf, Sebastian; Wagner, Dimitrios L.; Schulze, Veronika; Isaakidis, Konstandina; Lázaro-Navarro, Juan; Hänzelmann, Sonja; James, Alva Rani; Ekici, Arif B.; Burmeister, Thomas; Schwartz, Stefan; Schrappe, Martin; Horstmann, Martin; Vosberg, Sebastian; Krebs, Stefan; Blum, Helmut; Hecht, Jochen; Greif, Philipp A.; Rieger, Michael A.; Brüggemann, Monika; Gökbuget, Nicola; Neumann, Martin; Baldus, Claudia D.

doi:10.1038/s41375-019-0430-z

Cited by 49 publications

(76 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In none of the available remission samples PAX5 P80R was detectable, showing that PAX5 P80R is not a germline variant but rather somatically acquired. This confirms previous observations 15 …”

Section: Resultssupporting

confidence: 94%

See 1 more Smart Citation

Frequency and prognostic impact of PAX5 p.P80R in pediatric acute lymphoblastic leukemia patients treated on an AIEOP‐BFM acute lymphoblastic leukemia protocol

Jung

Schieck

Hofmann

et al. 2020

Genes Chromosomes & Cancer

Self Cite

View full text Add to dashboard Cite

PAX5 is a member of the paired box (PAX) family of transcription factors involved in B‐cell development. PAX5P80R has recently been described as a distinct genetic B‐cell precursor (BCP) acute lymphoblastic leukemia (ALL) subtype with a favorable prognosis in adults. In contrast, an unfavorable outcome has been observed in children. Our aim was to determine the frequency of PAX5P80R in childhood BCP‐ALL treated according to the Associazione Italiana Ematologia ed Oncologia Pediatrica‐Berlin‐Frankfurt‐Muenster (AIEOP‐BFM) ALL 2000 protocol and to evaluate its clinical significance within this study cohort. The analyses included 1237 patients with ALL treated in the AIEOP‐BFM ALL 2000 trial with complete information for copy number variations (CNVs) of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, and ERG. A customized TaqMan genotyping assay was used to screen for PAX5P80R. Sanger sequencing was used to confirm PAX5P80R‐positive results as well as to screen for second variants in PAX5. Agilent CGH + SNP arrays (e‐Array design 85 320; Agilent Technologies) were performed in PAX5P80R‐positive patients to verify additional CNVs. Almost 2% (20/1028) of our BCP‐ALL cohort were PAX5P80R‐positive. White blood cell counts higher than 50 000/μl as well as male sex were significantly (P < .05) associated with PAX5P80R. Most of the PAX5P80R‐positive cases were 10 years of age or older. PAX5P80R‐positive samples were enriched for deletions affecting PAX5, IKZF1, CDKN2A, and CDKN2B. Compared to PAX5P80R‐wildtype BCP‐ALL, PAX5P80R‐positive patients showed a significantly reduced 5‐year overall survival (P = .042). Further studies should evaluate the interaction of PAX5P80R with other genetic aberrations to further stratify intermediate risk pediatric BCP‐ALL.

show abstract

Section: Resultssupporting

confidence: 94%

“…PAX5 P80R has been the focus of interest of several other studies 13‐15,21 . While our research was focused on children, others have examined adults 13 or both 14,15 with opposing conclusions regarding outcome.…”

Section: Discussionmentioning

confidence: 99%

Frequency and prognostic impact of PAX5 p.P80R in pediatric acute lymphoblastic leukemia patients treated on an AIEOP‐BFM acute lymphoblastic leukemia protocol

Jung

Schieck

Hofmann

et al. 2020

Genes Chromosomes & Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…From a genomics standpoint, we detected a reduction in PAX5 gene dosage in the majority of samples that we tested thus far, which is reminiscent of our observation in TCF3-HLF 1 ALL. 5 In our cohort, events leading to PAX5 loss of function were primarily monoallelic, which is in contrast with the majority of the samples for 2 recently described entities in ALL, PAX5alt 1 and PAX5 P80R, 38 in which both alleles of PAX5 are generally affected. Indeed, VNN2 expression was also detected in the IKZF1 plus ALL subtype, which has been identified based on the combination of IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletions, marking a subtype with poor outcomes in patients with MRD MR ALL or MRD HR ALL.…”

Section: Discussioncontrasting

confidence: 67%

The hematopoietic stem cell marker VNN2 is associated with chemoresistance in pediatric B-cell precursor ALL

Bornhäuser

Cario²,

Rinaldi

et al. 2020

Blood Advances

Self Cite

View full text Add to dashboard Cite

Most relapses of acute lymphoblastic leukemia (ALL) occur in patients with a medium risk (MR) for relapse on the Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL protocol, based on persistence of minimal residual disease (MRD). New insights into biological features that are associated with MRD are needed. Here, we identify the glycosylphosphatidylinositol-anchored cell surface protein vanin-2 (VNN2; GPI-80) by charting the cell surface proteome of MRD very high-risk (HR) B-cell precursor (BCP) ALL using a chemoproteomics strategy. The correlation between VNN2 transcript and surface protein expression enabled a retrospective analysis (ALL-BFM 2000; N = 770 cases) using quantitative polymerase chain reaction to confirm the association of VNN2 with MRD and independent prediction of worse outcome. Using flow cytometry, we detected VNN2 expression in 2 waves, in human adult bone marrow stem and progenitor cells and in the mature myeloid compartment, in line with proposed roles for fetal hematopoietic stem cells and inflammation. Prospective validation by flow cytometry in the ongoing clinical trial (AIEOP-BFM 2009) identified 10% (103/1069) of VNN2+ BCP ALL patients at first diagnosis, primarily in the MRD MR (48/103, 47%) and HR (37/103, 36%) groups, across various cytogenetic subtypes. We also detected frequent mutations in epigenetic regulators in VNN2+ ALLs, including histone H3 methyltransferases MLL2, SETD2, and EZH2 and demethylase KDM6A. Inactivation of the VNN2 gene did not impair leukemia repopulation capacity in xenografts. Taken together, VNN2 marks a cellular state of increased resistance to chemotherapy that warrants further investigations. Therefore, this marker should be included in diagnostic flow cytometry panels.

show abstract

“…Most recently, novel subtypes of ALL based on diverse PAX5 alternation, including PAX5alt, PAX5 p.Pro80Arg, or PAX5-plus, were reported [49–51]. PAX5-plus patients, with PAX5 p.Pro80Arg as hotspot and biallelic genomic alterations, had a favorable treatment outcome in trials of population-based German study cohorts [50]. In contrast, the outcome for PAX5 p.Pro80Arg in children treated on St. Jude Total Therapy protocols was unfavorable [49].…”

Section: Discussionmentioning

confidence: 99%

Establishment and characterization of a novel childhood acute lymphoblastic leukemia cell line, HXEX-ALL1, with chromosome 9p and 17p deletions

et al. 2019

View full text Add to dashboard Cite

Background Although contemporary chemotherapy has improved the cure rate of childhood acute lymphoblastic leukemia (ALL) to nearly 90%, relapsed/refractory ALL is still a leading cause of tumor-related death in children. To clarify the underlying mechanisms of relapsed/refractory childhood ALL, researchers urgently need to establish novel cell models from patients with relapsed ALL after treatment with contemporary chemotherapy. Methods Cell culture technique was used to establish the HXEX-ALL1 cell line from primary B cell precursor ALL (BCP-ALL) cells. Molecular and cellular biological techniques including flow cytometry, polymerase chain reaction (PCR), short tandem repeat (STR) analysis, conventional cytogenetics, and chromosomal microarray analysis (CMA) were used to characterize the HXEX-ALL1 cell line. Nude mice were used for xenograft studies. Results A stable ALL cell line, HXEX-ALL1, derived from a 6-year-old boy of Han nationality with BCP-ALL at the second relapse, was established and maintained in culture for more than 18 months. The HXEX-ALL1 cell line was authenticated as being derived from primary leukemia cells based on morphologic, immunophenotypic, cytogenetic and STR analyses and demonstrated tumorigenicity in nude mice. WGS data showed that there were 27,006 novel single nucleotide polymorphisms (SNPs) and 193,951 novel insertion/deletions (InDels) in HXEX-ALL1 cells. Compared with the other BCP-ALL cell lines in use, the HXEX-ALL1 cells have a special karyotype represented by trisomy 8 and 9p and 17p deletions with a multidrug resistance phenotype, especially highly resistant to asparaginase. Conclusions The HXEX-ALL1 cell line may prove to be a useful model for the study of relapsed/refractory childhood ALL, particularly for the researches on asparaginase resistance.

show abstract

PAX5 biallelic genomic alterations define a novel subgroup of B-cell precursor acute lymphoblastic leukemia

Cited by 49 publications

References 50 publications

Frequency and prognostic impact of PAX5 p.P80R in pediatric acute lymphoblastic leukemia patients treated on an AIEOP‐BFM acute lymphoblastic leukemia protocol

Frequency and prognostic impact of PAX5 p.P80R in pediatric acute lymphoblastic leukemia patients treated on an AIEOP‐BFM acute lymphoblastic leukemia protocol

The hematopoietic stem cell marker VNN2 is associated with chemoresistance in pediatric B-cell precursor ALL

Establishment and characterization of a novel childhood acute lymphoblastic leukemia cell line, HXEX-ALL1, with chromosome 9p and 17p deletions

Contact Info

Product

Resources

About