Myelodysplastic syndrome (MDS) and Acute Myeloid Leukemia (AML) are hematologic malignancies associated with poor survival and limited treatment options. Clonal Hematopoiesis of Indeterminate Potential (CHIP), which is defined by the presence of an expanded clone with a mutation in an MDS/AML-associated gene in the blood of healthy individuals,1?4 is a premalignant state. A recent whole exome sequencing (WES) analysis completed by our lab of 70,000 healthy individuals identified additional mutated genes which may initiate CHIP, including zinc finger and broad-complex, tramtrak and bric-a-brac- domain-containing 33 (ZBTB33). Additionally, ZBTB33 mutations have been identified by our collaborators in patients with MDS. ZBTB33 was previously implicated as both a transcriptional activator and repressor, and it is unclear how its effect on transcription is regulated and/or if it has additional unknown roles in hematopoietic cells. In this work, I aim to establish a functional role for ZBTB33 loss in promoting clonal evolution and self- renewal of hematopoietic stem/progenitor cells (HSPCs). I also propose to elucidate the biological mechanism of these effects by characterizing how the disruption of individual ZBTB33 functional domains, in which the human mutations occur, alters ZBTB33's interactome. This work has the potential to identify and characterize a novel gene mutated in CHIP and MDS patients. Gaining insight into the biological mechanisms of CHIP and MDS initiation has the potential to impact the development of treatment and prevention strategies for these conditions.
Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a pre-disease state that precedes some blood cancers. The purpose of this work is to test if and how mutations in a specific gene, ZBTB33, initiate CHIP. This information may lead to new treatment and/or prevention strategies for blood cancers that currently have few treatment options and poor outcomes.