Mutational landscape and clinical outcome of pediatric acute myeloid leukemia with 11q23/KMT2A rearrangements

Abstract

Background Alterations of 11q23/KMT2A are the most prevalent cytogenetic abnormalities in acute myeloid leukemia (AML) and the prognostic significance of 11q23/KMT2A‐rearranged AML based on various translocation partners varies among different studies. However, few studies evaluated the molecular characteristics of 11q23/KMT2A‐rearranged pediatric AML. We aim to analyze the mutational landscape of 11q23/KMT2A‐rearranged AML and assess their prognostic value in outcomes. Methods The mutational landscape and clinical prognosis of 105 children with 11q23/KMT2A‐rearranged AML in comparison with 277 children with non‐11q23/KMT2A‐rearranged AML were analyzed using publicly accessible next‐generation sequencing data from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset. Results Pediatric AML patients with 11q23/KMT2A‐rearrangements harbored a low number of mutations (Median, 1 mutation/patient, range, 1‐22), 58% of which involved in RAS pathway mutations (KRAS, NRAS, and PTPN11) and 10.5% of which comprised of SETD2 mutations. Compared with non‐11q23/KMT2A‐rearranged AML, the incidence of KRAS (32.4% vs. 10.1%, P〈0.001) and SETD2 (10.5% vs. 1.4%, P=0.001) gene mutations in 11q23/KMT2A‐rearranged AML was significantly higher. Both KRAS and SETD2 mutations occurred more often in t(10;11)(p12;q23). KRAS mutations were correlated with worse 5‐year event‐free survival [EFS] (Plog‐rank = 0.001) and 5‐year overall survival [OS] (Plog‐rank = 0.009) and the presence of SETD2 mutations increases the 5‐year relapse rate (PGray = 0.004). Multivariate analyses confirmed KRAS mutations in 11q23/KMT2A‐rearranged AML as an independent predictor for poor EFS (hazard ratio [HR] = 2.10, P=0.05) and OS (HR = 2.39, P=0.054). Conclusion Our findings show that pediatric patients with 11q23/KMT2A rearrangements have characteristic mutation patterns and varying clinical outcomes depending on different translocation partners, which could be utilized to develop more accurate risk stratification and tailored therapies.

Single-cell analysis of pediatric acute myeloid leukemia samples uncovers treatment-resistant stem and mast cells

“…Of the 33 pAML subtypes, 11 were HSC-like (CD34 + ), eight GMP-like (AZU1 + , ELANE + ), eight monocyte-like (CD14 + , CD68 + , LYZ + ), three cDC-like (ITGAX + ), two mast-like (TPSAB1 + ) and one megakaryocyte-like (PPBP + ) (Fig 3D). Consistent with the diversity of KMT2A rearrangements 26 and "other" categories, 17 out of 21 patients formed patient-specific subtypes (>90% of cells in a subtype from one patient, Supplemental Figure 5). RUNX1, FLT3, and CBFB pAML subtypes overlapped between patients with only two out of sixteen patients forming patient-specific subtypes (Supplemental Figure 5).…”

“…To examine the association of CD69 + IGLL1 + HSC-like pAML with proliferation, we compared its gene signature score with clinical BM blast percentage in the TARGET AML data and observed a significant positive correlation (R=0. 26,p<0.05,Fig 4E). Thus, DE and pathway analysis indicated that CD69 + IGLL1 + HSC-like pAML promotes poor outcomes via proliferative and anti-apoptotic gene expression.…”

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development

“…Alterations of the KMT2A gene (also known as mixed lineage leukemia 1, MLL1 or MLL gene) located at 11q23.3 are found in both acute lymphoblastic leukemia (ALL) and AML, making up ∼10% of all leukemia cases in all age groups ( Winters and Bernt, 2017 ). KMT2A rearrangements ( KMT2A r) are one of the most common recurrent genetic aberrations found in 15%–25% of all newly diagnosed cases of pediatric AML ( Meyer et al, 2006 ; Meyer et al, 2009 ; Meyer et al, 2013 ; Meyer et al, 2018 ; Hoffmeister et al, 2021 ; Quessada et al, 2021 ; Meyer et al, 2023 ; Yuen et al, 2023 ). KMT2A r are particularly prevalent in infant AML, accounting for approximately 30% of children presenting below the age of 2 years.…”

Integration of Transcriptomic Features to Improve Prognosis Prediction of Pediatric Acute Myeloid Leukemia With KMT2A Rearrangement

“…4 However, this did not seem to work well in pediatric AML. Yuen et al 5 demonstrated pediatric AML with KMT2A::MLLT1 had higher overall survival (OS) and lower relapse rates than KMT2A::MLLT3 . Balgobind et al 6 identified AML with KMT2A::MLLT11 had excellent outcome and failed to confirm favorable outcome of KMT2A::MLLT3 in pediatric AML.…”