Abstract 3591: Inhibition of heme oxygenase 1 decreases proliferation and resensitizes TKI-resistant Flt3-ITD-positive AML cells

Acute myelogenous leukemia (AML) afflicts ∼12,330 new patients per year in the United States. Regrettably, only 25% of patients will survive five years past diagnosis. The most common mutation in AML is internal tandem duplication (ITD) of the juxtamembrane domain of the fms-like tyrosine kinase receptor-3 (Flt3), which renders it constitutively active. This mutation correlates with poor clinical prognosis and has been targeted therapeutically. Unfortunately, Flt3-directed tyrosine kinase inhibitors (TKI) have shown only modest benefit as single agents. Additionally, relapse and resistance are major factors in the treatment of Flt3-ITD+AML. In addition to its prominent role in regulating proliferative signaling, Flt3-ITD also increases production of reactive oxygen species (ROS) which act as secondary messengers, mediating oncogenesis and drug resistance. Heme oxygenase 1 (HO-1) is a ROS-responsive antioxidant that mediates proliferation and drug resistance in some cancer types. Initial analysis of patient samples from the AML TCGA cohort suggests that HO-1 is up-regulated in a subset of AML patients where its expression correlates with poor prognosis. Interestingly, HO-1 over-expression co-occurs with Flt3 receptor alterations. Thus, we hypothesized that Flt3-ITD-dependent signaling and ROS production increase HO-1, resulting in proliferation and drug resistance in AML. Constitutive expression of HO-1 protein and mRNA was elevated in murine (BaF3/Flt3-ITD) and human (MOLM1...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Experimental and Molecular Therapeutics Source Type: research