# Targeting the GFI1-LSD1 Axis in T-Cell Acute Lymphoblastic Leukemia

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $369,430

## Abstract

ABSTRACT
Growth Factor Independence 1 (GFI1) is a zinc-finger transcriptional repressor and master regulator of growth,
differentiation and survival in hematopoiesis. By repressing genes that favor cell cycle arrest and apoptosis,
GFI1 confers a growth and survival advantage to cells that express it. We have discovered that NOTCH1
intracellular domain (N1ICD) binds and stabilizes GFI1. N1ICD shields a consensus element for SUMOylation
embedded within the GFI1 linker, preventing SUMO-dependent polyubiquitination and degradation of GFI1.
Thymoctyes require GFI1 to withstand Notch activation during normal T-lymphopoiesis, while mutations that
favor unbridled Notch signaling cause T-cell acute lymphoblastic leukemia (T-ALL). GFI1 depletion triggers
apoptosis in T-ALL cells. These data implicate N1ICD—GFI1 binding as a pro-survival adaptation to
constitutive Notch activation and define GFI1 effectors and their recruitment mechanisms as novel, non-
redundant therapeutic inputs for T-ALL. GFI1's dominant effector is Lysine Specific Demethylase 1 (LSD1).
GFI1—LSD1 binding requires the GFI1 SNAG domain. Our proposed experiments focus on molecular
determinants of LSD1 recruitment by GFI1 and test LSD1 inhibition as a strategy to treat T-ALL. Aim #1:
Identify and define mechanisms governing integrity and function of the N1ICD—GFI1—LSD1 complex.
The GFI1 SNAG domain is required for GFI1—LSD1 binding, but alone it has limited affinity. However,
methylation on lysine (K) 8 in the -8KSKK11- motif of the SNAG domain profoundly favors SNAG—LSD1
binding. We will test the impact of K8 methylation on GFI1 function, identify methyltransferase(s) responsible
and determine how LSD1 inhibition modulates binding relationships among components of the complex. This
data informs mechanisms regulating complex integrity/function and may define an alternate inhibitory input for
the GFI1—LSD1 axis. Aim #2: Determine efficacy of the LSD1 inhibitor, SP-2577, toward T-ALL in vitro
and in vivo and identify candidate biomarkers of SP-2577 action. LSD1 inhibition is a rationally conceived
strategy to treat T-ALL. SP-2577 is a potent, selective, and reversible inhibitor of LSD1 developed at Huntsman
Cancer Institute that displays anti-proliferative, pro-apoptotic activity toward T-ALL cells. We will determine its
efficacy toward primary patient specimens and identify/validate biomarkers indicative of SP-2577 activity. Aim
#3: Determine the impact of GFI1—LSD1 binding on GFI1 pro-survival effects and SP-2577 efficacy in
T-ALL. GFI1 depletion and LSD1 inhibition phenocopy one another in growth and differentiation assays. Using
GFI1 and LSD1 derivatives that uncouple GFI1—LSD1 binding from LSD1 catalytic activity, we will determine if
GFI1 pro-survival effects and SP-2577 efficacy depend upon GFI1 bound to catalytically active LSD1. These
data inform mechanisms of cell survival in T-ALL and instruct us about the GFI—LSD1 axis as a target of
LSD1 inhibitors. Our studies provide critical i...

## Key facts

- **NIH application ID:** 10129907
- **Project number:** 5R01CA201235-05
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Michael E Engel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $369,430
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129907

## Citation

> US National Institutes of Health, RePORTER application 10129907, Targeting the GFI1-LSD1 Axis in T-Cell Acute Lymphoblastic Leukemia (5R01CA201235-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129907. Licensed CC0.

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