The genetic basis for pediatric acute myeloid leukemia (AML) is highly heterogeneous, often involving the cooperative action of characteristic chromosomal rearrangements and somatic mutations in progrowth and antidifferentiation pathways that drive oncogenesis. Although some driver mutations are shared with adult AML, many genetic lesions are unique to pediatric patients, and their appropriate identification is essential for patient care. The increased understanding of these malignancies through broad genomic studies has begun to risk-stratify patients based on their combinations of genomic alterations, a trend that will enable precision medicine in this population.
Pediatric acute myeloid leukemia (AML) has drivers that are unique to both infants and children as well as drivers found in common with adult AML.
Genetic profiling of pediatric acute myeloid leukemia can identify drivers that are diagnostic, prognostic, or predictive in a large majority of patients.
Profiling of pediatric megakaryoblastic leukemia identifies genetic alterations associated with a wide range of patient outcomes.
Acute myeloid leukemia (AML) is a biologically and genetically heterogeneous malignancy that accounts for approximately 20% of pediatric acute leukemias. With the development of optimized therapeutic regimens and allogeneic hematopoietic stem cell transplantation, overall survival rates of pediatric AML have approached 70% but still significantly lower than that of pediatric acute lymphoblastic leukemia (ALL). As with other hematological malignancies, pediatric AML has been evolving from a morphologic classification scheme to a genetically based one, aided by the rapid progression of molecular detection methods, such as next-generation sequencing (NGS).
The World Health Organization (WHO) currently recognizes several types of AML with recurrent genetic abnormalities, the extent of which is certain to grow with the explosion of genomic profiling studies in recent years. Although many of the recurrent genetic drivers of myeloid leukemia are found in common between pediatric and adult patients, the prevalence and clinical significance of these drivers differ depending on the age of the patient.
AML often is defined by the presence of recurrent chromosomal rearrangements that create chimeric fusion genes that promote AML development and progression. These fusions are diagnostic, prognostic, and, in some cases, predictive biomarkers that drive clinical management. These so-called class II alterations often involve transcription factors that serve to block differentiation of hematopoietic progenitor cells, which subsequently acquire cooperating mutations in other pathways, often tyrosine kinase or RAS, which are progrowth pathway mutations (class I mutations).
This review focuses on genetic variants found in AML that are most germane to clinical management of pediatric patients, while acknowledging that variants found more commonly in adults still can be found in pediatric patients.