Discussion
AML, death, hematological myeloid malignancies, myelofibrosis
ESSENTIAL THROMBOCYTHEMIA, OXIDATIVE STRESS, AML, MYELOFIBROSIS
Imetelstat is a first-in class telomerase inhibitor with clinical efficacies in hematological myeloid malignancies, including essential thrombocythemia, myelofibrosis and lower-risk myelodysplastic syndromesFerroptosis is a recently discovered type of non-apoptotic regulatory cell death that relies on the balance of the production of ROS during lipid peroxidation and the antioxidant system and it is generally characterized by three hallmarks: (1) loss of peroxide repair capacity through GPX4; (2) availability of redox-active iron; and (3) oxidation of polyunsaturated fatty acid-containing phospholipidsOur functional genetic experiments using Brunello library CRISPR/Cas9 editing have provided further evidence that imetelstat restricts leukemic progression via ferroptosis, revealing a closely related functional network of seven genes. One of the identified targets, ACSL4, has previously been identified as a key regulator of ferroptosis sensitivity through the shaping of the cellular lipid compositionG-quadruplexes are recognized by and regulate the activity of many proteins involved in telomere maintenance, replication, transcription, translation, mutagenesis and DNA recombinationUsing a newly established, comprehensive AML patient-derived xenograft resource that reflects the overall genetic abnormalities found in large clinical cohorts, we demonstrated a proof of concept for the sequential administration of standard induction chemotherapy followed by imetelstat consolidation to induce oxidative stress and sensitize AML patient samples to imetelstat treatment. This approach was able to cause significant delay or prevention of AML relapse. The efficacy of sequential therapy suggests that imetelstat may be particularly useful in preventing relapse after chemotherapy, for example, as a maintenance therapy. Recently, maintenance therapy with oral CC486 has shown a survival benefit in AML; however, there is no survival plateau and therefore, most patients still relapse and die of their diseaseIn conclusion, imetelstat is a potent inducer of ferroptosis that effectively diminishes AML burden and delays relapse following oxidative stress-inducing chemotherapy.Clinical trials will address the efficacy of imetelstat in AML and may focus on this compound as a consolidation strategy for preventing relapse or potentially together with targeted therapies to improve outcomes in patients with AML.