# Understanding Ikaros molecular functions for targeted therapies of pre-B ALL

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $361,667

## Abstract

ABSTRACT
Blood cancer constitutes nearly 10% of all newly diagnosed cancer cases in the US and is the leading cause of
cancer mortality for children and young adults. Leukemia is a cancer of developing progenitor blood cells, and
the most common subtype of leukemia in pediatric patients is the precursor B-cell acute lymphoblastic
leukemia (pre-B ALL) subtype. While treatment for pre-B ALL has improved greatly in recent years, there are
still subtypes of leukemia that have poor prognosis and limited treatment options, and relapse remains a
significant problem. Some of these subtypes can be characterized by specific genetic lesions. Mutations or
deletions in the IKZF1 gene encoding the transcription factor Ikaros define one such high-risk subgroup. Ikaros
is critical for lymphoid development and is recognized as an important tumor suppressor in pre-B ALL, in
particular in BCR-ABL1+ (Ph+) pre-B ALL, where Ikaros loss-of-function mutations are found in greater than
80% of cases, and in the newly defined high-risk BCR-ABL1-negative “Ph-like” subclass. In spite of the well-
documented role of Ikaros as a tumor suppressor in pre-B ALL, there is limited understanding of how Ikaros
functions to suppress leukemia. Furthermore, the molecular mechanisms underlying the strong association
between the BCR-ABL1 oncogene and loss of Ikaros tumor suppressor function is poorly understood.
Importantly, there are currently no therapies available that target Ikaros loss-of-function in pre-B ALL. We
propose to study the unique features of Ikaros-mutated Ph+ leukemia in order to aid in rational design of
targeted therapies, and we will focus on key aspects of Ikaros function. First, as Ikaros mutations are shown to
result in aberrant expression of progenitor-restricted genes (including `stemness' genes), we will test the
functional role of selected cell-surface proteins aberrantly expressed in Ikaros-mutated pre-B ALL, and
evaluate their growth- or survival-promoting properties (Aim 1). Second, we will study the mechanism of Ikaros
as a regulator of chromatin structure and ultimately investigate if epigenetic inhibitors can be employed to
mimic Ikaros tumor suppressor function in IKZF1-mutated pre-B ALL (Aim 2). Furthermore, we will investigate
the specific collaboration between the BCR-ABL1 oncogene and IKZF1-mutations by evaluating if Ph+ pre-B
ALL has a specific chromatin accessibility signature enabeled by IKZF1-mutations that is required for the
downstream BCR-ABL1 pathways (Aim 3). The results of this study may provide new functional targets for
diagnosis and treatment of IKZF1-mutated pre-B ALL, and will provide critical insight into epigenetic
dysregulation in leukemia for the rational use of epigenetic modulators for treatment.

## Key facts

- **NIH application ID:** 9966923
- **Project number:** 5R01CA230618-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Seth E Frietze
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $361,667
- **Award type:** 5
- **Project period:** 2018-07-25 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966923

## Citation

> US National Institutes of Health, RePORTER application 9966923, Understanding Ikaros molecular functions for targeted therapies of pre-B ALL (5R01CA230618-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9966923. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*