Skip to main content
Publications of the Week

Control of Focal Adhesion Kinase Activation by RUNX1-Regulated miRNAs in High-Risk AML

By March 9, 2023No Comments

Read the Publication

This week we profile a recent publication in Leukemia from the lab of Dr. Aly Karsan (pictured, back row, centre) at Canada’s Michael Smith Genome Sciences Centre and UBC with first author Dr. Vijay Akhade (back row, far right).

Can you provide a brief overview of your lab’s current research focus?

The major focus of my lab is to understand the mechanisms of refractoriness to therapy and the reasons for relapse in acute myeloid leukemias and preleukemias, such as the myelodysplastic syndromes. We are particularly interested in the influence of aging and inflammation in therapy resistance, and are now using various single cell approaches to unravel the complexity of interactions between the microenvironment leukemic cells and the interactions between leukemic cells. We have also done a significant amount of work to deliver genomic and biomarker testing into the clinic. To this end, we recently we published a validated clinical transcriptome-based assay, where we developed an gene expression-based prognosticator (Docking et al, Nat Commun, 2021). In this work, we found that a subset of high-risk patients were defined by activation of cell adhesion pathways including focal adhesion kinase encoded by the PTK2 gene. We also noted that loss of function mutations of either RUNX1 or TP53 resulted in induction of PTK2, and cells with these mutations were sensitive to PTK2 inhibitors.

What is the significance of the findings in this publication?

In the above studies, even though RUNX1 loss of function resulted in PTK2 induction, this was not through a direct mechanism. In the current work, we performed micro(mi)RNA sequencing on the same samples used in development of the clinical transcriptome assay, with the thought that reduced expression RUNX1-targeted miRNAs may derepress PTK2 expression. Examination of paired RNA-seq and miRNA-seq data from 301 AML cases revealed two miRNAs that positively correlated with RUNX1 expression, contained RUNX1-binding sites in their promoters and were predicted to target PTK2. We showed that the hsa-let7a-2-3p and hsa-miR-135a-5p promoters are regulated by RUNX1, and that PTK2 is a direct target of both miRNAs. Even in the absence of RUNX1 mutations, hsa-let7a-2-3p and hsa-miR-135a-5p regulated PTK2 expression, and reduced expression of these two miRNAs and sensitized AML cells to PTK2 inhibition. These data explain how RUNX1 regulates PTK2, and importantly identify potential miRNA biomarkers for targeting AML with PTK2 inhibitors.

What are the next steps for this research?

We have been communicating with an Australian group conducting a clinical trial of PTK2 inhibitors in AML, and are hoping to conduct correlative studies to determine whether these miRNAs can be used as biomarkers to predict which AML patients will respond to PTK2 inhibitors.

If you’d like to mention your funding sources, please list them.

Canadian Institutes of Health Research, Terry Fox Research Institute, Leukemia and Lymphoma Society of Canada, Genome BC

Read the Publication