R01CA271455

Dissecting Innate Immune Signaling in Pre-Leukemia Evolution - Abstract

Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of mutated pre-leukemic cells. Although individuals with CH are healthy, they are at an increased risk of developing hematopoietic malignancies.

To identify cooperating molecular alterations required for malignant transformation of clonal pre-leukemic HSPC, we performed an in vivo shRNA screen. We found that shRNAs targeting TRAF6 were overwhelmingly enriched following transformation to overt myeloid leukemias. TRAF6 is an ubiquitin E3 ligase that synthesizes lysine (K) 63-linked ubiquitin chains on substrates, leading to Toll-like receptor (TLR) superfamily pathway activation.

In support of our in vivo shRNA screen, promoter hypermethylation and reduced expression of TRAF6 is observed in subsets of myeloid malignancy patients, including approximately 40-50% of acute myeloid leukemia (AML). Moreover, our preliminary data shows that deletion of TRAF6 in pre-leukemic TET2-deficient HSPC results in an aggressive myeloid neoplasm, in part through a novel MYC-dependent mechanism.

Based on our findings, we hypothesize that loss of TRAF6 drives subsets of genetically-defined myeloid malignancies, specifically via a novel post-translational modification of MYC resulting in its activation.

The objectives of the proposal are to uncover the molecular and cellular basis of TRAF6 deletion on pre-leukemic HSPC function, with the long-term goal of uncovering improved therapeutic approaches. This will be achieved by investigating the consequences of TRAF6 deletion in models of CH and on leukemia development (Aim 1), identifying the molecular basis of the tumor suppressor-like function of TRAF6 in AML (Aim 2), and evaluating the oncogenic potential of a novel TRAF6-dependent MYC post-translational modification (Aim 3).

These studies are highly significant as they will provide critical insight into the progression of pre-leukemic states to overt leukemia as a result of subverting select innate immune pathways. They also describe a novel disease-modifying role of TLR-TRAF6 and reveal an unreported mechanism of MYC regulation.

These studies have direct translational implications and fill an unmet clinical need for genetically- and phenotypically-defined subtypes of AML/MPN.

Childrens Hospital Medical Center

TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

Cincinnati, Ohio 45229 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 384% from $652,991 to $3,161,289.