For patients with AML, identification of their specific subtype and genetic background is crucial for predicting their outlook and decision of treatment. Therefore, understanding the molecular characteristics of specific subtypes of AML can lead to novel therapeutics and improve patient survival.
The present invention relates to a unique vulnerability of AML subtypes, in which specific chromosome abnormalities result in the dependence of the cancer cells on the activity of native RUNX1. Selective inhibition of RUNX1 under these genetic backgrounds results in killing of the cancer cells. Thus, the methods described in this innovation may lead to the development of novel AML therapeutics.
- Specificity targets a signaling vulnerability which is unique to AML and does not occur in healthy cells.
- Critical impact the inhibition of RUNX1 in addicted cells induces irreversible killing of the cancer cells by apoptosis rather than just inhibiting their proliferation.
- Targeting RUNX1 in the addicted AML subtypes can potentially improve patient survival and also be used as a therapy for patients which developed secondary resistance in response to conventional chemotherapy.
The RUNX1 transcription factor is a frequent target of various chromosomal translocations.
The t(8;21) and inv(16) AML subtypes create oncoproteins which interfere with RUNX1 activity in a dominant-negative manner.
While RUNX1 is frequently inactivated in other forms of AML, an active RUNX1 allele is maintained in both t(8;21) and inv(16) AML patients, underscoring the medical significance of native RUNX1 in A-E and C-S mediated leukemogenesis.
Knockdown (KD) of RUNX1 in cell culture models for A-E and C-S showed that these cells are physiologically dependent on RUNX1 activity for their survival and inhibition of RUNX1 in these cells leads to apoptotic cell death. This apoptosis is triggered by decreased expression of key mitosis-regulatory gene.
Therefore, AML subtypes associated with an altered RUNX1 activity or expression are addicted to native RUNX1 for their survival. Targeting RUNX1 in these patients is expected to activate apoptosis and compromise leukemogenesis.
Thus, the genetic addiction described in the current innovation can be used for the development of novel targeted therapies for AML.