Introduction

Researchers have recently identified ZFP91 as a critical ZFP91 myeloid leukemia regulator that drives EVI1 expression. Historically, clinicians linked EVI1 overexpression primarily to 3q26 chromosomal rearrangements. However, this study reveals how EVI1 levels remain high in many patients even without these specific genetic abnormalities. Consequently, these findings offer a fresh biological explanation for the poor clinical outcomes observed in a broader range of myeloid leukemia cases.

Ecotropic viral integration site 1 (EVI1) is a transcription factor that maintains hematopoietic stem cell function. Unfortunately, it becomes highly oncogenic when overexpressed in myeloid cells. While chromosomal rearrangements typically cause this elevation, many leukemia cases display high EVI1 levels despite possessing a normal 3q26 locus. To solve this clinical mystery, researchers utilized genome-wide CRISPR screening. They successfully discovered that zinc finger protein 91 (ZFP91) acts as the primary activator of EVI1 in these contexts.

The Mechanism of the ZFP91 Myeloid Leukemia Regulator

Mechanistically, ZFP91 binds directly to the EVI1 promoter region. This binding actively enhances crucial histone modifications, specifically H3K4me3 and H3K27ac. Additionally, it significantly increases chromatin accessibility, which facilitates aggressive gene transcription. Furthermore, the study demonstrated that knocking out ZFP91 effectively reduced leukemia cell proliferation and EVI1 expression levels. Therefore, the ZFP91-EVI1 axis represents a promising new therapeutic target for patients facing EVI1-positive myeloid malignancies.

Frequently Asked Questions

Why is EVI1 significant in myeloid leukemia?

EVI1 is essential for maintaining hematopoietic stem cells, but its aberrant overexpression is a major indicator of poor prognosis and therapy resistance in myeloid leukemia.

How does ZFP91 influence EVI1 expression?

ZFP91 acts as a transcriptional activator that binds to the EVI1 promoter, enhancing active chromatin marks like H3K4me3 and H3K27ac to drive gene expression.

What are the clinical implications of these findings?

The identification of the ZFP91-EVI1 axis suggests that ZFP91 could be a target for future therapies, especially for patients who overexpress EVI1 without traditional chromosomal rearrangements.

Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice or a professional relationship. Always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Refer to the latest local and national guidelines for clinical practice.

References

Hayashida H et al. Genome-wide screening identifies ZFP91 as a key regulator of EVI1 in myeloid leukemia. Oncogene. 2026 Apr 25. doi: 10.1038/s41388-026-03727-7. PMID: 42034869.

Unoki M et al. Identification of a novel human gene, ZFP91, involved in acute myelogenous leukemia. Int J Oncol. 2003 Jun;22(6):1213-9. PMID: 12738987.

Glass C et al. Global Identification of EVI1 Target Genes in Acute Myeloid Leukemia. PLoS ONE. 2013;8(6):e67134. doi: 10.1371/journal.pone.0067134.