KMT2A (alias: mixed-lineage leukemia [MLL]) gene mapping on chromosome 11q23 encodes the lysine-specific histone N-methyltransferase 2A and promotes transcription by inducing an open chromatin conformation. Numerous genomic breakpoints within the KMT2A gene have been reported in young children and adults with hematologic disorders and are present in up to 10% of acute leukemias. These rearrangements describe distinct features and worse prognosis depending on the fusion partner, characterized by chemotherapy resistance and high rates of relapse, with a progression-free survival of 30–40% and overall survival below 25%. Less intensive regimens are used in pediatric patients, while new combination therapies and targeted immunotherapeutic agents are being explored in adults. Beneficial therapeutic effects, and even cure, can be reached with hematopoietic stem cell transplantation, mainly in young children with dismal molecular lesions; however, delayed related toxicities represent a concern. Herein, we summarize the translocation partner genes and partial tandem duplications of the KMT2A gene, their molecular impact, clinical aspects, and novel targeted therapies.

Background: Current chronic lymphocytic leukemia (CLL) International Prognostic Index (IPI) stratifies patients based on clinical, molecular, and biochemical features; however, B‐cell markers also influence CLL outcomes. Here, prognostic roles of CD11c, CD38, and CD49d were first evaluated, and then an immunophenotypic score was combined with CLL‐IPI for risk stratification of CLL patients.Methods: A total of 171 CLL subjects were included, and surface marker expression was assessed by flow cytometry. Levels ≥30% were chosen as cut‐off of positivity to a marker; then values of 1 (for CD11c and CD38) or 3 (for CD49d) were assigned and scores determined for each patient's clone immunophenotype.Results: CD49d positivity was significantly associated with simultaneous expression of CD11c and/or CD38, unmutated IGHV status, and higher β2‐microglobulin levels compared to those with CD49d negativity. Moreover, CD49d⁺ patients experienced a shorter progression‐free survival and time to treatment. When the immunophenotypic score was combined with CLL‐IPI, patients with high‐risk immunophenotype had a significantly lower time‐to‐treatment regardless CLL‐IPI.Conclusions: Our results suggested clinical utility of an integrated prognostic score for better risk stratification of CLL patients. These results require further validation in prospective larger studies.

There was an error in the original publication

BCOR and BCORL1 (BCOR/L1 ) mutations are observed in both myeloid neoplasms (MN) and bone marrow failure syndromes (BMF), but their clinical significance may differ. We analyzed 11 340 patients and identified 418 BCOR/L1 ‐mutated patients, focusing on differences between MN and BMF. Compared with MN, BMF was associated with younger age, a higher frequency of normal karyotype, a greater proportion of missense mutations, and significantly lower variant allele frequencies (VAFs). We next compared BCOR/L1 ‐mutated cases with wild‐type cases. In MN, BCOR/L1 mutations were associated with older age, inferior survival, and a higher number of co‐occurring mutations, whereas in BMF, they were associated with a higher prevalence of PNH clones. Single‐cell DNA sequencing and VAF‐based analysis demonstrated that BCOR/L1 mutations were usually secondary in MN but primary events in BMF. Longitudinal sequencing revealed that BCOR/L1 ‐mutant clones often contracted or disappeared over time, even in progression, suggesting limited clonal fitness of BCOR/L1 mutations themselves; instead, progression was associated with increased mutational burden, particularly in RUNX1 . Prognostically, BCOR/L1 mutations were associated with inferior survival in MN, whereas in BMF they were not associated with prognosis and tended to correlate with a favorable response to immunosuppressive therapy. RNA‐sequencing analyses showed reduced BCOR/L1 expression in BMF, and BCOR knockout was associated with reduced HLA class I expression. Our findings suggest that BCOR/L1 mutations are secondary events in MN and co‐occurring mutations may influence disease progression and prognosis, whereas in BMF they appear to be ancestral events acquired independently of progression to MN, potentially through immune privilege‐related mechanisms.