The Impact of Zbtb7a and Zbtb7b Loss in Acute Myeloid Leukemia Drug Resistance

Meryl McKenna

Document Type

Article

Publication Date

Summer 2023

Keywords

JGM

JAX Location

In: Student Reports, Summer 2023, The Jackson Laboratory

Abstract

Acute myelogenous leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of differentiation. Novel therapeutic approaches for AML include the use of differentiation-based therapies. However, leukemia cells typically gain resistance to treatment, a main reason for low survival rate of AML patients. Previous work in the Wang lab identified specific genes involved in AML differentiation resistance through comprehensive genome-wide CRISPR screening. Notably, the loss of one of those genes, namely ZBTB7A, was shown to confer resistance to differentiation-based AML therapies in the human cellular models. Here, the present study represents a logical extension of this research by examining the potential role of Zbtb7a and family member Zbtb7b gene knockouts within the context of a mouse MLL-AF9 Nras model. The objective of this investigation is to validate the important role of these gene paralogs for AML differentiation in vitro to enable future evaluation in vivo. The results show that Zbtb7a knockout both inhibits differentiation and causes resistance to the differentiation agent, Vitamin D3. Zbtb7b knockout demonstrates a similar phenotype, raising the possibility of a synergistic effect with double gene knockout and establishing a foundation for in vivo testing.

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