Abstract
This review aims to provide an overview of the current knowledge of the genetic lesions driving pediatric acute myeloid leukemia (AML), emerging biological concepts, and strategies for therapeutic intervention. Hereby, we focus on lesions that preferentially or exclusively occur in pediatric patients and molecular markers of aggressive disease with often poor outcome including fusion oncogenes that involve epigenetic regulators like KMT2A, NUP98, or CBFA2T3, respectively. Functional studies were able to demonstrate cooperation with signaling mutations leading to constitutive activation of FLT3 or the RAS signal transduction pathways. We discuss the issues faced to faithfully model pediatric acute leukemia in mice. Emerging experimental evidence suggests that the disease phenotype is dependent on the appropriate expression and activity of the driver fusion oncogenes during a particular window of opportunity during fetal development. We also highlight biochemical studies that deciphered some molecular mechanisms of malignant transformation by KMT2A, NUP98, and CBFA2T3 fusions, which, in some instances, allowed the development of small molecules with potent anti-leukemic activities in preclinical models (e.g., inhibitors of the KMT2A–MENIN interaction). Finally, we discuss other potential therapeutic strategies that not only target driver fusion-controlled signals but also interfere with the transformed cell state either by exploiting the primed apoptosis or vulnerable metabolic states or by increasing tumor cell recognition and elimination by the immune system.
Highlights
Specialty section: This article was submitted to Pediatric Hematology and Hematological Malignancies, a section of the journal Frontiers in Pediatrics
We focus on lesions that preferentially or exclusively occur in pediatric patients and molecular markers of aggressive disease with often poor outcome including fusion oncogenes that involve epigenetic regulators like KMT2A, nucleoporin 98 (NUP98), or CBFA2/RUNX1 translocation partner 3 (CBFA2T3), respectively
The TARGET acute myeloid leukemia (AML) initiative provided a comprehensive dataset of genetic alterations in pediatric AML that confirmed and extended previous observations indicating that similar to adult patients, pediatric AML is the product of a low number of cooperating mutations frequently involving transcriptional regulators affecting differentiation and selfrenewal properties and mutations of signaling mediators [9] (Figure 1)
Summary
Molecular hematology–oncology starting in the 1970s of the last century was heavily influenced by the pioneering work of Janet Rowley and others that used conventional cytogenetics followed by the upcoming recombinant DNA technology to show that, in addition to other structural lesions, balanced chromosomal translocations frequently lead to expression of fusion genes [1]. In landmark studies by Timothy Ley and members of the Cancer Genome Atlas Research Network, the genome of a single AML patient was obtained in 2008 They later sequenced the whole genome of 24 selected AML cases and the exomes of the progeny of hematopoietic stem and progenitor cells (HSPCs) taken from seven healthy individuals of different age [5, 6]. The Children’s Oncology Group (COG)– National Cancer Institute (NCI) TARGET AML initiative was able to characterize the genomic landscape of almost 1,000 pediatric AML patients by whole genome sequencing of samples from 197 and targeted sequencing of tumor cells from 800 patients [8] This extensive effort revealed similarities and important differences between adult and pediatric AML. We focused on hallmarks of aggressive pediatric AML fusion oncogenes, including KMT2A, CBFA2T3, and NUP98 fusions
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