Search Results (3)

KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL), particularly in infants, represents one of the most aggressive pediatric hematological malignancies with a historically dismal prognosis. While KMT2A-AFF1 (t(4;11)) is the most prevalent fusion, a diverse array of partner genes exists, each conferring distinct biological and clinical features. This review focuses on the rare but clinically significant KMT2A-AFF3 subtype, which arises from the t(2;11)(q11.2;q23) chromosomal translocation. This review summarizes the molecular pathogenesis driven by the KMT2A-AFF3 fusion oncoprotein, which functions as an aberrant transcriptional complex. This complex hijacks essential epigenetic machinery, including the recruitment of DOT1L and interaction with Menin, leading to pathogenic histone modifications (e.g., H3K79 hypermethylation) and the subsequent upregulation of critical target genes, notably the HOXA cluster and MEIS1, thereby enforcing a B-lymphoid differentiation arrest at the pro-B/pre-B stage. Clinically, KMT2A-AFF3 ALL is characterized by high-risk features, including infant onset, hyperleukocytosis, central nervous system (CNS) involvement, and a distinct CD10-negative immunophenotype. This review highlights the evidence defining its poor prognosis, which is primarily driven by profound chemoresistance to conventional therapies, including glucocorticoids. Finally, we discuss the rapidly evolving therapeutic landscape, detailing the limitations of standard intensive chemotherapy and the immense promise of novel targeted strategies, such as Menin inhibitors (e.g., Revumenib), DOT1L inhibitors, and immunotherapies (e.g., CAR-T cells, Blinatumomab), which hold the potential to revolutionize outcomes for this high-risk leukemia subtype. Full article

The KMT2A/AFF1 rearrangement is associated with an unfavorable prognosis in infant acute lymphocytic leukemia (ALL). Discordant ALL in monozygotic twins is uncommon and represents an attractive resource to evaluate intrauterine environment–genetic interplay in ALL. Mutational and epigenetic profiles were characterized for a discordant KMT2A/AFF1-rearranged infant monozygotic twin pair and their parents, and they were compared to three independent KMT2A/AFF1-positive ALL infants, in which the DNA methylation and gene expression profiles were investigated. A de novo Q61H NRAS mutation was detected in the affected twin at diagnosis and backtracked in both twins at birth. The KMT2A/AFF1 rearrangement was absent at birth in both twins. Genetic analyses conducted at birth gave more insights into the timing of the mutation hit. We identified correlations between DNA methylation and gene expression changes for 32 genes in the three independent affected versus remitted patients. The strongest correlations were observed for the RAB32, PDK4, CXCL3, RANBP17, and MACROD2 genes. This epigenetic signature could be a putative target for the development of novel epigenetic-based therapies and could help in explaining the molecular mechanisms characterizing ALL infants with KMT2A/AFF1 fusions. Full article

Background: This study evaluates the main (para)clinical aspects and outcomes in a group of Romanian children diagnosed with acute lymphoblastic leukemia (ALL), under the conditions of antileukemic treatment according to an adapted ALL IC Berlin–Frankfurt–Munster (BFM) 2002 protocol. Methods: We performed a retrospective single-center study of 125 children diagnosed with ALL between 2010 and 2016. Standard forms were used for data collection of variate clinical and paraclinical parameters. Results: The children were predominantly male (64.8%) and their median age at diagnosis was 5 years. A total of 107 patients were diagnosed with precursor B-cell acute lymphoblastic leukemia (BCP)-ALL and 18 with T-cell acute lymphoblastic leukemia T-ALL. Multiplex reverse transcription polymerase chain reaction RT-PCR assay for ETV6-RUNX1, BCR-ABL, E2A-PBX1, KMT2A-AFF1, and STIL-TAL1 fusion genes was performed in 111 patients. ETV6-RUNX1 translocation was detected in 18.9% of patients, while BCR-ABL1 and E2A-PBX1 rearrangements were seen in 2.7% and 3.6%, respectively. Complete remission at the end of induction phase was obtained in 89.6% of patients. The overall relapse rate was 11.2%, with 11 early and 3 late relapses. The 5-year overall survival rate in BCP-ALL was 81.6% and in T-ALL 71.4%. Conclusions: The 5-year overall and event-free survival rates in our study were slightly lower than those reported in developed countries, so the patients’ outcomes are encouraging. Full article