# Mechanisms of KLF4 suppression in pediatric leukemia

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $370,641

## Abstract

Project Summary
Acute lymphoblastic leukemia (ALL) is the most prevalent hematological cancer in children younger than 14
years of age. Although disease relapse is the leading cause of cancer-related death in pediatric cancer
patients, little progress has been made in the treatment of leukemia relapse or in reducing the incidence of
relapse by increasing the cure rates of frontline therapy. The prognosis of children with second and third
marrow relapse is poor with complete remission rates of 44% and 27% respectively. Thus, the development of
targeted therapies in T-ALL is a clear priority in pediatric oncology. A poor understanding of the mechanism by
which leukemia-initiating cells (LIC) drive chemoresistance and relapse has hindered the development of
therapies targeting this population. We discovered that Krüppel-like factor 4 (KLF4) is inactivated by gene
methylation in T cell ALL (T-ALL) patients and that deletion of the Klf4 gene in mice accelerates the
development of NOTCH1-induced T-ALL by promoting LIC expansion. As a transcriptional repressor, loss of
KLF4 augments the expression of the dual specificity mitogen-activated protein kinase 7 (Map2k7) and
consequently activates JNK and downstream ATF2 and c-Jun. In sharp contrast to wild-type T-ALL mice and
healthy children, we discovered elevated protein levels in the total and phosphorylated Map2k7, and
downstream activation of the JNK pathway, both in KLF4-deficient murine T-ALL and pediatric T-ALL patients.
Thus, the loss of KLF4 in mouse is an ideal model with which to study the inhibition of the Map2k7 pathway
aberrantly activated in human T-ALL. Based on our strong preliminary data our central hypothesis is that
inactivation of KLF4 in T-ALL patients augments Jnk-dependent expansion of LIC by increasing the levels of
Map2k7 and that pharmacological inhibition of this pathway can ameliorate disease progression and potentially
eradicate disease. In order to prove this hypothesis, we will conduct three specific aims: (Aim 1) Investigate
KLF4 regulation of the Map2k7 pathway using the genetic mouse model of NOTCH1-induced T-ALL and
patient samples to validate Map2k7 for LIC-targeted therapy; (Aim 2) Study the molecular mechanism
underlying regulation of LIC self-renewal and the downstream amino acid response mechanism driving
chemoresistance; (Aim 3) Study the anti-leukemic properties of Map2k7 and JNK inhibition as single agents
and in combination with standard chemodrugs in pre-clinical models using the genetic mouse model and
patient-derived xenografts of pediatric T-ALL. Our studies are likely to have a large overall impact on the field
of leukemia because they will fundamentally advance our mechanistic understanding of leukemogenesis and
LIC self-renewal and chemoresistance. Thus, this study will contribute to the eradication of this deadly disease
in children and adolescents by defining the mechanisms required for the maintenance of LICs during T-ALL
progression and evaluating new ...

## Key facts

- **NIH application ID:** 9870882
- **Project number:** 5R01CA207086-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Daniel Lacorazza
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,641
- **Award type:** 5
- **Project period:** 2017-03-09 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870882

## Citation

> US National Institutes of Health, RePORTER application 9870882, Mechanisms of KLF4 suppression in pediatric leukemia (5R01CA207086-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9870882. Licensed CC0.

---

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