# Ikaros regulation: study on hemo-lymphopoiesis

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $414,024

## Abstract

ABSTRACT
Ikaros deficient large pre-B cells show attenuation of pre-BCR signaling and differentiation and an increase in
stroma adhesion, and self-renewal. Ikaros plays a fundamentally unique role in the regulation of both active
and cryptic Super-Enhancer networks (SE) in pre-B cells. Active SE supporting pre-B cell differentiation are
defined by Ikaros and other B cell master regulators. However, they are uniquely dependent on Ikaros for their
highly permissive chromatin environment and transcription activity. Ikaros, without any B cell transcription
factors, is highly enriched at inactive enhancers of genes normally expressed in epithelial-stem cells. Upon
Ikaros loss, expression of pre-B cell differentiation genes is attenuated, while a group of extra-lineage
transcription factors, directly repressed by Ikaros, is induced. These collaborate with native B cell transcription
regulators to induce a hybrid SE network that supports epithelial cell functions. This model of a dual
mechanism of IKAROS regulation in promoting normal B cell differentiation while safeguarding against an
epithelial-B cell phenotype and how deregulation contributes to B-ALL is investigated by three specific aims.
Specific Aim 1. Regulation of pre-B cell super-enhancers and chromosomal domains. The role of Ikaros
in the recruitment of chromatin modifiers and the mediator complex, key steps in SE activation, will be tested.
We will also investigate whether Ikaros promotes the segregation of developmentally-affiliated genes into
topological associated domains (TAD) domains.
Specific Aim 2. Regulation of a cryptic transcriptional network in pre-B cells. Ikaros is engaged in the
active repression of a regulatory network of transcription factors in WT pre-B cells that are normally prevalent
in epithelial tissues. The contribution of these extra-lineage transcription factors to an epithelial-pre-B cell
phenotype will be examined in the absence and presence of Ikaros. We will also investigate whether Ikaros
provides an additional layer of protection by directly interfering with their activities at their enhancer target sites.
Specific Aim 3. How a pre-leukemic transcriptional landscape is utilized for leukemia progression.
Activating mutations in tyrosine kinases affiliated with growth factor receptor signaling support transformation
of Ikaros mutant pre-B cells to a highly aggressive leukemic state. A key question addressed here is whether
and how the leukemia-inducing signaling pathways utilize the epigenetic and transcription environment
established by loss of Ikaros. Further studies on the potential conservation of these mechanisms in human B-
ALL will be tested.

## Key facts

- **NIH application ID:** 9933994
- **Project number:** 5R01HL140622-27
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** KATIA GEORGOPOULOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $414,024
- **Award type:** 5
- **Project period:** 2011-09-05 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933994

## Citation

> US National Institutes of Health, RePORTER application 9933994, Ikaros regulation: study on hemo-lymphopoiesis (5R01HL140622-27). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9933994. Licensed CC0.

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