Pediatric acute lymphoblastic leukemia (pALL) is the most common childhood malignancy, yet its etiology remains incompletely understood. However, over the course of three waves of germline genetic research, several non-environmental causes have been identified. Beginning with trisomy 21, seven overt cancer predisposition syndromes (CPSs)-characterized by broad clinical phenotypes that include an elevated risk of pALL-were first described. More recently, newly described CPSs conferring high risk of pALL are increasingly covert, with six exhibiting only minimal or no non-cancer features. These 13 CPSs now represent the principal known hereditary causes of pALL, and human pangenomic data indicates a strong negative selection against mutations in the genes associated with these conditions. Collectively they affect approximately 1 in 450 newborns, of which just a minority will develop the disease. As evidenced by tailored leukemia care protocols for children with trisomy 21, there is growing recognition that CPSs warrant specialized diagnostic, therapeutic, and long-term management strategies. In this review, we investigate the evidence that the 12 other CPSs associated with high risk of pALL may also see benefits from specialized care - even if these needs are often incompletely mapped or addressed in the clinic. Given the rarity of each syndrome, collaborative international research and shared data initiatives will be crucial for advancing knowledge and improving outcomes for these patients.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * genetics   etiology   MeSH
• Child MeSH
• Genetic Predisposition to Disease * MeSH
• Humans MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Genetic lesions of IKZF1 are frequent events and well-established markers of adverse risk in acute lymphoblastic leukemia. However, their function in the pathophysiology and impact on patient outcome in acute myeloid leukemia (AML) remains elusive. In a multicenter cohort of 1606 newly diagnosed and intensively treated adult AML patients, we found IKZF1 alterations in 45 cases with a mutational hotspot at N159S. AML with mutated IKZF1 was associated with alterations in RUNX1, GATA2, KRAS, KIT, SF3B1, and ETV6, while alterations of NPM1, TET2, FLT3-ITD, and normal karyotypes were less frequent. The clinical phenotype of IKZF1-mutated AML was dominated by anemia and thrombocytopenia. In both univariable and multivariable analyses adjusting for age, de novo and secondary AML, and ELN2022 risk categories, we found mutated IKZF1 to be an independent marker of adverse risk regarding complete remission rate, event-free, relapse-free, and overall survival. The deleterious effects of mutated IKZF1 also prevailed in patients who underwent allogeneic hematopoietic stem cell transplantation (n = 519) in both univariable and multivariable models. These dismal outcomes are only partially explained by the hotspot mutation N159S. Our findings suggest a role for IKZF1 mutation status in AML risk modeling.

• MeSH
• Leukemia, Myeloid, Acute * pathology   MeSH
• Adult MeSH
• Humans MeSH
• Mutation MeSH
• Nucleophosmin MeSH
• Prognosis MeSH
• Ikaros Transcription Factor genetics   MeSH
• Transcription Factors genetics   MeSH
• Hematopoietic Stem Cell Transplantation * MeSH
• fms-Like Tyrosine Kinase 3 genetics   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• IKZF1 protein, human MeSH Browser
• Nucleophosmin MeSH
• Ikaros Transcription Factor MeSH
• Transcription Factors MeSH
• fms-Like Tyrosine Kinase 3 MeSH

BACKGROUND: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL-positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1-deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers. METHODS: Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1. Quantitative PCR assays were designed and used to re-measure MRD in remission bone marrow samples previously tested using Ig/TCR markers. All MRD testing complied with EuroMRD guidelines. RESULTS: ABL-class patients had 46% 5year event-free survival and 79% 5year overall survival. All had sensitive fusion tests giving high concordance between Ig/TCR and ABL-class fusion results (21 patients, n = 257 samples, r2 = 0.9786, P < 0.0001) and Ig/TCR and IKZF1-deletion results (9 patients, n = 143 samples, r2 = 0.9661, P < 0.0001). In contrast, in BCR-ABL1 patients, Ig/TCR and BCR-ABL1 tests were discordant in 32% (40 patients, n = 346 samples, r2 = 0.4703, P < 0.0001) and IKZF1-deletion results were closer to Ig/TCR (25 patients, n = 176, r2 = 0.8631, P < 0.0001). CONCLUSIONS: MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1-deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * genetics   MeSH
• Fusion Proteins, bcr-abl * genetics   MeSH
• Child MeSH
• Immunoglobulins MeSH
• Humans MeSH
• Receptors, Antigen, T-Cell genetics   MeSH
• Neoplasm, Residual genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Fusion Proteins, bcr-abl * MeSH
• Immunoglobulins MeSH
• Receptors, Antigen, T-Cell MeSH

Novel biological subtypes and clinically important genetic aberrations (druggable lesions, prognostic factors) have been described in B-other acute lymphoblastic leukemia (ALL) during the last decade; however, due to a lack of studies on unselected cohorts, their population frequency and mutual associations still have to be established. We studied 110 consecutively diagnosed and uniformly treated childhood B-other patients using single nucleotide polymorphism arrays and whole exome/transcriptome sequencing. The frequency of DUX4-rearranged, BCR-ABL1-like, ZNF384-rearranged, ETV6-RUNX1-like, iAMP21 and MEF2D-rearranged subtypes was 27%, 15%, 5%, 5%, 4%, and 2%, respectively; 43% of cases were not classified into any of these subtypes (B-rest). We found worse early response to treatment in DUX4-rearranged leukemia and a strong association of ZNF384-rearranged leukemia with B-myeloid immunophenotype. Of the druggable lesions, JAK/STAT-class and RAS/RAF/MAPK-class aberrations were found in 21% and 43% of patients, respectively; an ABL-class aberration was found in one patient. A recently described negative prognostic factor, IKZF1plus , was found in 14% of patients and was enriched in (but not exclusive for) BCR-ABL1-like subtype. PAX5 fusions (including 4 novel), intragenic amplifications and P80R mutations were mutually exclusive and only occurred in the B-rest subset, altogether accounting for 20% of the B-other group. PAX5 P80R was associated with a specific gene expression signature, potentially defining a novel leukemia subtype. Our study shows unbiased European population-based frequencies of novel ALL subtypes, recurrent (cyto)genetic aberrations and their mutual associations. This study also strengthens and widens the current knowledge of B-other ALL and provides an objective basis for optimization of current genetic diagnostics.

• MeSH
• Chromosome Aberrations * MeSH
• Child MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Genomics methods   MeSH
• Cohort Studies MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation * MeSH
• Biomarkers, Tumor genetics   MeSH
• Follow-Up Studies MeSH
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma epidemiology   genetics   pathology   MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Transcriptome * MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Europe MeSH
• Names of Substances
• Oncogene Proteins, Fusion MeSH
• Biomarkers, Tumor MeSH