Post-Transcriptional Regulation is a Therapeutic Vulnerability of Acute Myeloid Leukemia

/ABSTRACT Acute myeloid leukemia (AML) has persistently maintained a low ~32% 5-year survival rate in spite of over three decades of medical research. With approximately 22,010 in the U.S being diagnosed with AML and 11,090 dying from the disease yearly, there remains an urgent need to develop new therapies and treatment strategies. Understanding the key protein drivers of AML and the regulatory mechanisms governing expression of these proteins has provided us with an opportunity to specifically target the disease. The most common variants of AML in both pediatric and adult patients depend upon the chromatin binding MLL protein complex. Recently developed small molecule menin-inhibitors have demonstrated remarkable clinical success by inhibiting MLL complex formation. However, close to 40% of patients treated with menin inhibitors for prolonged periods develop resistance and subsequently relapse, demonstrating an urgent need for combination therapy. Our lab has previously shown that a critical component of the MLL complex, LEDGF, is sensitive to perturbations in translation due to its short half-life. I demonstrated that LEDGF protein expression can be inhibited with the RNA helicase eIF4A1 inhibitor silvestrol, and that silvestrol has potent anti -AML properties. The following aims will test the hypothesis that eIF4A1 inhibition is an effective AML therapy in vivo, capable of circumventing menin inhibitor resistance. In Aim 1 I will generate novel mouse models of menin inhibitor resistant adult and pediatric AML to test the efficacy of eIF4A1 inhibition as an AML therapy. In Aim 2 I will identify the molecular mechanisms by which eIF4A1 contributes to LEDGF translation, exploring the role of eIF4A1 in maintaining AML cells. The long-term objectives of this project are to characterize a clinically relevant new approach to treat AML and uncover molecular mechanisms governing mRNA translation. This fellowship application is sponsored by Dr. Daisuke Nakada, PhD, an expert in hematopoietic stem cell biology and acute myeloid leukemia biology. This training plan is designed to 1) provide mentorship from experts in science and medicine; 2) develop general and field-specific scientific knowledge in stem cell, chromatin, and RNA biology; 3) grow my scientific communication skills and form professional networks; and 4) develop clinical skills and knowledge toward a pediatrician-scientist career. The clinical and scientific training environment is at Baylor College of Medicine, located in the heart of the Texas Medical Center with close ties to institutions such as Texas Children's Hospital and MD Anderson Cancer Center. This environment is ideal to foster scientific and clinical growth toward my long-term goal of becoming a physician scientist in the field of pediatric hematology-oncology. Project Number: 1F30CA310107-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Jacob Tao | Institution: BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX | Award Amount: $54,107 | Activity Code: F30 | Study Section: Special Emphasis Panel[ZRG1 F09A-R (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11316067