New research suggests the cell of origin controls the aggressiveness and outcome of acute myeloid leukemia (AML) driven by MLL-AF9.
Using a mouse model, investigators found that MLL-AF9 expression in long-term hematopoietic stem cells (HSCs) causes invasive, chemoresistant AML that expresses genes related to epithelial-mesenchymal transition (EMT).
The researchers also found these genes were associated with poor survival in humans with AML.
“The prognosis thus depends on the particular hematopoietic stem or precursor cells in which the genetic alteration occurs and what genes are expressed,” said Antoine Peters, PhD, of Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland.
Dr Peters and his colleagues related these findings in Cancer Cell.
The investigators compared the results of MLL-AF9 expression in long-term HSCs and granulocyte-macrophage progenitors (GMPs) in vitro. They found that colonies derived from long-term HSCs exhibited a greater capacity to migrate and expressed genes known to be involved in cell migration and tissue invasion.
With in vivo experiments, the researchers found that long-term HSCs were more potent in inducing AML than GMPs. Twenty percent of long-term HSC-derived AMLs proved especially aggressive, exhibiting extensive tissue infiltration, resistance to chemotherapy, and the expression of EMT genes such as EVI1, ERG, and ZEB1.
The investigators then tested the function of EMT-related transcription factors in leukemic cell migration and invasion. And they found that knocking down ZEB1 significantly reduced leukemic blast invasion.
Next, the researchers classified mouse and human leukemias according to EVI1/Evi1 and ERG/Erg expression and compared transcriptional profiles between species.
This revealed 111 genes that were more highly expressed in EVI1highERGhigh AML and Evi1highErghigh iMLL-AF9 long-term-HSC-early AML. These genes were dubbed ‘‘cluster I.’’
The investigators also identified 40 genes that were more highly expressed in EVI1lowERGlow AML samples and in iMLL-AF9 GMP-derived AML. These were called ‘‘cluster II.’’
Finally, the team evaluated how the 2 gene clusters related to overall survival in patients with 11q23+ AML.
Patients with high expression of cluster I genes tended to have poor survival rates, while patients with high levels of cluster II genes had variable survival rates and a propensity for poor outcomes if they had co-expression of a “substantial fraction” of cluster I genes.
The researchers noted that many cluster I genes are implicated in cell migration, invasion, EMT, and inflammation.
“The expression of genes such as EVI1, ERG, or ZEB1 now allows us to classify patients into different groups according to prognosis and, if necessary, to adapt treatment,” said Jürg Schwaller, MD, of University Children’s Hospital and University of Basel in Switzerland.
“Our findings should also enable us to develop new, more personalized therapies for these patients.”
