The biology of pediatric acute megakaryoblastic leukemia

Abstract

Acute megakaryoblastic leukemia (AMKL) comprises between 4% and 15% of newly diagnosed pediatric acute myeloid leukemia patients. AMKL in children with Down syndrome (DS) is characterized by a founding GATA1 mutation that cooperates with trisomy 21, followed by the acquisition of additional somatic mutations. In contrast, non-DS-AMKL is characterized by chimeric oncogenes consisting of genes known to play a role in normal hematopoiesis. CBFA2T3-GLIS2 is the most frequent chimeric oncogene identified to date in this subset of patients and confers a poor prognosis.

Figure 1

DS-AMKL pathogenesis. In utero truncating mutations in GATA1 lead to a TMD in the neonatal period that resolves in the absence of treatment. Residual cells either undergo apoptosis or acquire additional cooperating mutations leading to overt AMKL with an average latency of 3 years. Recurrently targeted genes include but are not limited to cohesin complex components, CTCF, the PRC2 complex, and kinase-signaling genes. Of the 26 sequenced DS-AMKL cases that carry mutations in cohesin, 6 contained mutations in a PRC2 complex gene as well as a kinase as shown in this example. Cohesin mutation, ●; GATA1 mutation, ★; kinase mutation, ▲; PRC2 mutation, ▪; Trisomy 21, ×××.

Figure 2

JAK signaling in megakaryopoiesis. Cytokine binding to its cellular receptor leads to dimerization and phosphorylation that in turn binds and activates JAK, leading to downstream activation of RAS signaling and phosphorylation of STAT transcription factors. Receptors and kinases with activating mutations identified in AMKL include MPL, PDGFRB, JAK1, JAK2, JAK3, NRAS, and KRAS. Mutations in SH2B3 have been identified in DS-AMKL. SHC1, adapter molecule; SH2B3, inhibitor of JAK2.

Figure 3

Key genomic events in non–DS-AMKL. A total of 142 pediatric non–DS-AMKL cases were analyzed for the presence of fusion gene events by transcriptome sequencing, reverse-transcription polymerase chain reaction (RT-PCR), or split-signal fluorescence in situ hybridization. A total of 96 samples were evaluated for the presence of the MLL-PTD by RT-PCR and 46 samples were evaluated for the presence of somatic GATA1 single-nucleotide variations and insertion/deletion by exome and/or Sanger sequencing. The proportion of MLL-PTD and GATA1 mutant cases was calculated based on the total number of samples evaluated for each of the lesions. Patients carrying GATA1 mutations did not have stigmata of DS or evidence of mutant reads in germline DNA, suggesting they are not mosaics. Cases that did not undergo transcriptome sequencing and were negative by RT-PCR for CBFA2T3-GLIS2, NUP98-KDM5A, RBM15-MKL1, and MLL rearrangements (MLLr) are designated as unknown. “Other fusion” includes single cases of each of the following: GATA2-HOXA9, NIPBL-HOXB9, MN1-FLI1, HLXB9-ETV6, FUS-ERG, and RUNX1-CBFA2T3. Data compiled from Gruber et al and de Rooij et al.