GENOMIC AND TRANSCRIPTOMIC PROFILING REVEALS NOVEL BIOMARKERS IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA
Péterffy Borbála
Pathological and Oncological Divison
Dr. Matolcsy András
SE I sz. Patológiai és Kísérleti Rákkutató Intézet, Arányi Lajos terem
2025-11-27 14:30:00
Molekuláris és experimentális onkológia
Dr. Bödör Csaba
Dr. Alpár Donát
Dr. Szarvas Tibor
Dr. Szuhai Károly
Dr. Fekete Andrea
Dr. Kocsmár Ildikó
Dr. Butz Henriett
Disease progression, relapse, and the detection of leukemic involvement of the central nervous system still raise prominent obstacles in the clinical management of ALL. The revolution of molecular genetics reshaped the field of diagnostics and risk assessment, and paved the way for targeted therapies, hence it was placed in the center of my PhD research.
Diagnostic bone marrow samples from 192 patients diagnosed with B-ALL/LBL (n=153) or T-ALL/LBL (n=39), and 92 CSF samples of 35 children with B-ALL/LBL (n=28) or T-ALL/LBL (n=7) were investigated. Additionally, samples drawn at the time of relapse were analysed from 19 patients. Comprehensive genomic and transcriptomic profiling was performed using TruSight RNA Pan-Cancer Panel targeting 1,385 genes, QIASeq Targeted DNA Custom Panel covering 103 disease-relevant genes, and MLPA or digitalMLPA, using the D007 ALL probemix. Copy numbers of miR-181a, miR-532 and miR-16 were quantified in the CSF using digital droplet PCR.
Novel fusions, involving JAK2, PAX5, KMT2A and RUNX1 genes were observed, with KMT2A-rearranged patients showing the worst prognosis (3-year EFS: 24 months, p=0.013). Targeted deep sequencing revealed somatic mutations in 74.9% of the patients. B-ALL patients harboring TP53 (p=0.008) or CREBBP (p=0.010) mutation displayed inferior EFS, and B-ALL patients with negative MRD at day 33 of therapy exhibited shorter EFS in the presence of TP53 (p<0.001) mutation.
By combining the cytospin- and flow cytometry (FCM)-derived data with the miR-181a expression, we were able to reclassify patients into three novel groups representing CNSL status, and assign previously ambiguous cases. CNSpos/miRsign patients had overt CNS infiltration, CNSmin/miRsign patients had potentially clinically significant, but latent CNSL, while CNSmin/miRmin group had no sign of CNS involvement. ROC analysis revealed a diagnostic value of miR-181a quantification surpassing cytospin and comparable to FCM. SH2B3 mutations were solely present in patients classified as miRsign.
Our work uncovers novel gene fusions and the prognostic importance of TP53 and CREBBP mutations and demonstrates a novel biomarker in the field of CNSL diagnostics, offering valuable, therapeutically relevant insight into the genomic and transcriptomic landscape of children diagnosed with ALL.
