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

Abstract

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.

Bone Marrow Stromal Cell Regeneration Profile in Treated B-Cell Precursor Acute Lymphoblastic Leukemia Patients: Association with MRD Status and Patient Outcome

“…In order to gain further insight into the potential role of BM stromal cells on the outcome of BCP-ALL, we investigated the prognostic impact of the distribution of such cells in childhood BCP-ALL at different time points after starting therapy, compared to other wellestablished prognostic factors such as MRD [32,[58][59][60][61][62][63][64][65][66][67][68][69] and tumor cytogenetics [70][71][72][73][74]. Interestingly, our results showed that increased percentages of EC within stromal cells found at day +78 of therapy identified a poorer prognosis subgroup of childhood BCP-ALL, independently of the BM MRD status.…”

A prognostic approach on a case of pediatric Philadelphia chromosome‐positive acute lymphoblastic leukemia with monosomy‐7

“…26 Germline mutations are demonstrated as the main drivers of Li-Fraumeni syndrome, which predisposes to a diverse range of inherited rare cancers. 25 Mutations in other genes such as RAS, PAX5, PTEN, EGFR, or MSH6 are involved as predictive markers for poor prognosis in cancers such as pediatric B and T ALL, [27][28][29] AML, 30 gastric adenocarcinoma, 31 glioblastoma, and brain tumors. 32,33 The reported case had relapsed within the first year following the achievement of remission and died after receiving intensive chemotherapy combined with imatinib.…”

“…Germline mutations are demonstrated as the main drivers of Li‐Fraumeni syndrome, which predisposes to a diverse range of inherited rare cancers 25 . Mutations in other genes such as RAS , PAX5 , PTEN , EGFR , or MSH6 are involved as predictive markers for poor prognosis in cancers such as pediatric B and T ALL, 27–29 AML, 30 gastric adenocarcinoma, 31 glioblastoma, and brain tumors 32,33 …”

B‐cell acute lymphoblastic leukaemia: recent discoveries in molecular pathology, their prognostic significance, and a review of the current classification

“…PAX5 p.P80R confers a poor prognosis in children but is suggested to have a relatively good prognosis in adults. 49,86,87 Taking a broader approach, results from a 250 patient European study advocated 'PAX5-plus' as a new entity, to denote biallelic PAX5 alterations, together with CDKN2A/B deletions and RAS-activating mutations. This group is suggested to have favourable outcomes.…”

“…Mutations in PAX5 are often associated with copy number neutral LOH or deletion of the wild‐type allele, and frequently co‐occur with mutations in the RAS or JAK‐STAT pathways as well as FLT3 , BRAF and PIK3CA . PAX5 p.P80R confers a poor prognosis in children but is suggested to have a relatively good prognosis in adults 49,86,87 …”