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Defining the roles of ZBTB7 paralogs in leukemogenesis

Award Number: K99CA315586
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/15/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Defining the roles of ZBTB7 paralogs in leukemogenesis - PROJECT SUMMARY/ABSTRACT Defects in cellular proliferation can lead to a variety of developmental disorders as well as cancer. This dysregulation is achieved through deleterious mutations of tumor suppressor genes (TSGs). However, tumor suppressors can be non-genetically inactivated, which is difficult to detect with standard genomic techniques. While some TSG somatic mutations have been identified in hematologic malignancies, there is a critical gap in knowledge for the role of TSG silencing in leukemogenesis. This study will examine how TSGs are inactivated at the post-transcriptional level in acute myeloid leukemia (AML) and how their restoration is a novel therapeutic avenue for leukemic elimination. I found that the transcriptional repressor ZBTB7A is post-transcriptionally silenced in AML, blocking differentiation in the myeloid lineage. This is achieved through alternative polyadenylation, resulting in an isoform with a longer 3’UTR that leads to deadenylation. I was able to restore ZBTB7A expression through epigenetic targeting of upstream negative regulators as a proof of concept of TSG re-activation. During the training (K99) phase of this award, I will uncover the exact RNA-binding proteins mediating downregulation of ZBTB7A, and if this is part of a larger pro-AML regulatory network blocking differentiation. To this end, we are employing a novel long read sequencing method termed Pull-a-Long Sequencing (PL-Seq) in collaboration with Dr. Pedro Miura, to uncover the roles of ZFP36 and ELAVL family members on the transcriptional stability of ZBTB7A. ZBTB7A has two paralogs in mammals, ZBTB7B and ZBTB7C. ZBTB7B has been implicated in hematopoietic differentiation of the lymphoid lineage, and the DNA-interacting residues of its zinc fingers are highly conserved to ZBTB7A. During the independent (R00) phase, I will apply the insights and tools acquired during the training phase to identify the contribution of ZBTB7B paralogs with ZBTB7A, and ascertain if they are synergistic in mediating myeloid differentiation. In my preliminary data, I have utilized a Rosa26LSL-Cas9-eGFP mouse model to delete Zbtb7a in the murine hematopoietic system and found that loss of Zbtb7a results in hematopoietic stem and progenitor (HSPC) expansion, as well as a bias in myeloid differentiation. With the guidance of Dr. Jennifer Trowbridge, an expert in mouse modeling of the hematopoietic system, I will more fully characterize Zbtb7a hematopoietic specific knockout mice as well as Zbtb7b knockout mice. Together, this will open multiple lines of inquiry into a family of transcriptional repressors and the role of non-genetic inactivation of tumor suppressors. My proposed study will generate novel tools and testable hypotheses that will lay a strong foundation for my independent research program, where I will continue to characterize non-genetic mechanisms of AML regulation as novel means for therapeutic intervention.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $136,687 )
2026	2026	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Research Manpower	000	1	7/15/2026	NEW	$136,687
														Subtotal = $136,687

Grand Total All Awards = $136,687

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Defining the roles of ZBTB7 paralogs in leukemogenesis

Award Number: K99CA315586

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/15/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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