ABSTRACT
Pediatric therapy-related myeloid neoplasms (tMN) occur in children after exposure to cytotoxic therapy and have a dismal prognosis. The somatic and germline genomic alterations that drive these myeloid neoplasms in children and how they arise have yet to be comprehensively described. We use whole exome, whole genome, and/or RNA sequencing to characterize the genomic profile of 84 pediatric tMN cases (tMDS: n = 28, tAML: n = 56). Our data show that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements are frequent somatic drivers, and we identify cases with aberrant MECOM expression secondary to enhancer hijacking. Unlike adults with tMN, we find no evidence of pre-existing minor tMN clones (including those with TP53 mutations), but rather the majority of cases are unrelated clones arising as a consequence of cytotoxic therapy. These studies also uncover rare cases of lineage switch disease rather than true secondary neoplasms.
Subject(s)
Leukemia, Myeloid, Acute/genetics , Neoplasms, Second Primary/genetics , Child , Gene Expression Regulation, Neoplastic , Genomics , Histone-Lysine N-Methyltransferase , Humans , Leukemia, Myeloid, Acute/therapy , Mutation , Myelodysplastic Syndromes , Myeloid-Lymphoid Leukemia Protein , Neoplasms, Second Primary/therapy , Prognosis , Exome SequencingABSTRACT
Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A. However, the etiology of 30-40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.
Subject(s)
Down Syndrome/genetics , Leukemia, Megakaryoblastic, Acute/genetics , Animals , Exome/genetics , Female , Gene Rearrangement/genetics , Genomics/methods , Humans , Mice , Mice, Inbred C57BL , Polymorphism, Single Nucleotide/genetics , RNA/genetics , Repressor Proteins/genetics , Retinoblastoma-Binding Protein 2/genetics , Tumor Suppressor Proteins/geneticsABSTRACT
Warm-reactive IgM autoimmune hemolytic anemia is uncommon and carries a poor prognosis in adults. There have been rare reports in children, generally associated with an underlying immunologic deficiency, and outcomes are quite variable. Warm IgM in combination with other antibodies has not been reported in children. We report the first case of severe, steroid-responsive autoimmune hemolytic anemia caused by both warm-reactive IgM and IgA autoantibodies in an otherwise healthy 3-month-old.
