The Impact of the Cellular Origin in Acute Myeloid Leukemia: Learning From Mouse Models

Abstract

Acute myeloid leukemia (AML) is a genetically heterogeneous disease driven by a limited number of cooperating mutations. There is a long-standing debate as to whether AML driver mutations occur in hematopoietic stem or in more committed progenitor cells. Here, we review how different mouse models, despite their inherent limitations, have functionally demonstrated that cellular origin plays a critical role in the biology of the disease, influencing clinical outcome. AML driven by potent oncogenes such as mixed lineage leukemia fusions often seem to emerge from committed myeloid progenitors whereas AML without any major cytogenetic abnormalities seem to develop from a combination of preleukemic initiating events arising in the hematopoietic stem cell pool. More refined mouse models may serve as experimental platforms to identify and validate novel targeted therapeutic strategies.

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

“…Notably, there is increasing evidence that the fetal and adult hematopoietic hierarchies significantly differ in structure and composition (97). Although not yet demonstrated in murine models of pediatric AML, several AML oncogenes (including KMT2A–MLLT3) studied in an adult context are able to transform both HSC and more committed progenitors (e.g., GMP) while others are not able to do so (67, 98–101). Also, as indicated above, the phenotype of KMT2A–MLLT3 + and KMT2A–MLLT1 + leukemia was dependent on the stage of the hematopoietic hierarchy in which the driver mutation was expressed (68, 69).…”

“…Functional cooperation studies in cellular and animal models suggest that we can group AML-associated mutations into drivers that are essential for induction and maintenance of the disease, and cooperating mutations that support expansion of the malignant clone or may facilitate transformation by mostly metabolic modifications (101). As a consequence, inactivation or degradation of the driver might represent the most promising approach for long-term cure of the disease.…”

Acute Myeloid Leukemia: From Biology to Clinical Practices Through Development and Pre-Clinical Therapeutics

“…Elderly cluster represents higher TCR clonality, higher OX40 expression in cytotoxic and Treg and higher CD45RO + T-cells, as well as lower naïve and central memory CD27 + , memory CD25 + and late-stage CD57 + cytolytic T-cells. Clonality trends were found to be associated with complex karyotypes and higher ELN risk but failed to show a significance due to the insufficient number of patients studied, while an association between T-cell lineage and AML gene mutations has been reported (15,57). Notably, although FLT3-mutated AML reportedly displays dendritic cells and Treg expansion, Teff are able to perform effector functions in the absence of an enriched Treg population (75).…”

“…Recently, AML pathogenesis has been modeled by expression of distinct leukemia-associated mutations ( 15 ). “TYPE-A mutations” (expression of AML-associated fusion genes such as MLL, CBF or RARA fusions) are necessary to maintain transformed phenotypes.…”

“…Studies based on mouse models have highlighted that AML, driven by potent oncogenes, such MLL fusion, may have developed via committed myeloid progenitors (CMP) whereas AML without any major cytogenetic abnormalities may emerge due to a combination of preleukemic initiating events arising in the hematopoietic stem cell (HSC) pool ( 15 ). Strong oncogenes mostly originate in CMPs, following which a few cooperating mutations may enable development of AML.…”