Abstract
Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia but is approximately 500 times more likely to develop in children with Down syndrome (DS) through transformation of transient abnormal myelopoiesis (TAM). This study investigates the clinical significance of genomic heterogeneity of AMKL in children with and without DS and in children with TAM. Genomic evaluation of nine patients with DS-related TAM or AMKL, and six patients with non-DS AMKL, included conventional cytogenetics and a comprehensive next-generation sequencing panel for single-nucleotide variants/indels and copy-number variants in 118 genes and fusions involving 110 genes. Recurrent gene fusions were found in all patients with non-DS, including two individuals with complex genomes and either a NUP98–KDM5A or a KMT2A–MLLT6 fusion, and the remaining harbored a CBFA2T3–GLIS2 fusion, which arose from both typical and atypical cytogenetic mechanisms. These fusions guided treatment protocols and resulted in a change in diagnosis in two patients. The nine patients with DS had constitutional trisomy 21 and somatic GATA1 mutations, and those with DS-AMKL had two to four additional clinically significant somatic mutations. Comprehensive genomic characterization provides critical information for diagnosis, risk stratification, and treatment decisions for patients with AMKL. Continued genetic and clinical characterization of these rare cancers will aid in improving patient management.
Highlights
Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML), defined by the presence of at least 50% of blasts from the megakaryocytic lineage, and patients often present with thrombocytopenia or thrombocytosis
Given that this patient’s prior therapy for B-cell acute lymphoblastic leukemia (B-ALL) did not include any cytotoxic therapies known to be associated with therapy-related AML, it was hypothesized that his AMKL may be a de novo AML, the possibility of a therapy-related AML could not be excluded
transient abnormal myelopoiesis (TAM) and Down syndrome (DS)-AMKL are characterized by trisomy 21 and GATA1 frameshift mutations with additional cytogenetic and sequence mutations observed in Down Syndrome–Related AMKL (DS-AMKL) exclusively
Summary
Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML), defined by the presence of at least 50% of blasts from the megakaryocytic lineage, and patients often present with thrombocytopenia or thrombocytosis. AMKL is typically observed in children, accounting for 4%–15% of AML cases, compared to
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