Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention

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.

An Immune Checkpoint-Related Gene Signature for Predicting Survival of Pediatric Acute Myeloid Leukemia

“…AML is a malignant haematological disorder, with a rise in prevalence with age, and 70% of patients also die from the disease diagnosed [26]. Immune therapy advances have been met with many challenges for children and adults with AML, including lack of identified tumor-specific antiquities, interand intrapatient disease heterogeneity [27], as well as greater Journal of Oncology understanding of microenvironmental factors impeding the therapeutic effectiveness of immunosuppressive bone marrows [28].…”

A validated pediatric disease risk index for allogeneic hematopoietic cell transplantation

“…[14][15][16] Cytogenetic abnormalities not accounted for in our analysis, such as NUP98, and CBFA2T3 fusions are more common in the very young with AML and carry an adverse prognosis. 4,[17][18][19][20][21] Thus, they too may benefit from targeted treatments, with or without transplantation. 22,23 Data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) study confirm that pediatric AML is molecularly diverse and lend support for the development of personalized treatments.…”

Increased risk of leukaemia in children with Down syndrome: a somatic evolutionary view

“…Mutations in epigenetic regulators and CTCF , which directly interacts with cohesins, are known to disrupt the expression of genes involved in HSC renewal and differentiation by chromatin modifications (Refs 44 , 45 ). Both the JAK-STAT pathway and RAS signalling pathway are involved in the regulation of cell proliferation, survival and differentiation (Refs 46 , 47 ). Mutations in these genes have been identified in different haematological malignancies and have been shown to contribute to the proliferation of leukaemic blasts (Refs 46 , 47 ).…”

“…Both the JAK-STAT pathway and RAS signalling pathway are involved in the regulation of cell proliferation, survival and differentiation (Refs 46 , 47 ). Mutations in these genes have been identified in different haematological malignancies and have been shown to contribute to the proliferation of leukaemic blasts (Refs 46 , 47 ). In conclusion, mutations in these genes could all result in increased cell survival, cell proliferation and impairments in the differentiation of the oncogenic clone (Refs 42 , 46 , 47 ).…”