Rui Su, PhD
Assistant Professor, Department of Systems Biology
Beckman Research Institute of the City of Hope
Research project
The Role of TET2 in Modulating Leukemia Stem Cell Homing and Reprogramming Immune Response
Summary
Acute myeloid leukemia (AML) is one of the most common blood cancers in the United States with over 20,050 new cases and 11,540 deaths estimated in 2022. Despite the considerable advances, the five-year survival rate of AML patients is still lower than 30%. Ten Eleven Translocation 2 (TET2) is recurrently deleted and/or mutated in 15-20% AML patients and TET2 deficiency leads to poorer prognosis and drug resistance. Therefore, it’s unmet medical to develop novel efficient approach to cure AMLs, especially the patients with TET2 mutation. Very recently, we have discovered that TET2 deficiency facilitates the homing of leukemia stem cells (LSCs) into the bone marrow (BM) niche to support their self-renewal and initiate leukemogenesis. LSCs is responsible for AML relapse and chemotherapy, and eliminating LSCs has been recognized as the “holy grail” of anti-leukemia treatment. Moreover, we also identified that loss of TET2 leads to the immune evasion of AML cells from CD8+ T cell surveillance in leukemia microenvironment. In this proposal, my lab aims to systemically delineate the role of TET2 in LSC homing and leukemia immunity and reveal the underlying molecular mechanism(s). We believe that the better understanding of TET2 in AML BM microenvironment will substantially contribute to the development of more specific and efficient therapies against the very aggressive AMLs with TET2 deficiency.
Impact
This project provides compelling biological data to determine how TET2 determines target mRNA fate and modulates target mRNA expression (e.g., TSPAN13) at the post-transcriptional level as an m5C “eraser”. In addition, it also interprets the underlying mechanism by which TET2 plays a crucial role in regulating anti-leukemia immunity.
Standard “7+3” induction therapy, a combination of ara-C and anthracycline, has been broadly applied for AML therapy for more than 40 years. However, with currently available therapeutics, over 70% of AML patients cannot survive more than 5 years. TET2 is frequently mutated in 15-20% of AML patients and those patients are always with much poorer prognosis. Thus, there is an urgent and unmet medical need to develop improved therapeutics for AML treatment, particularly for patients with TET2 deficiency.
This project may lead to the establishment of effective novel therapeutic strategies to treat TET2-mutant or -low AMLs by blocking LSC/LIC homing, eradicating LSCs/LICs, and regulating T cell toxicity. As a result, the success of this project may lead to the launching of first-in-human clinical trials to treat unfavorable-risk AMLs with TET2 deficiency, which are resistant to currently available therapeutics.
Publication
Leukemia Research Foundation grant
$100K awarded in 2022
Disease focus
Acute myeloid leukemia (AML)
Research focus
Cancer cell biology (leukemia stem cells)