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 Krppel-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 therapeutic approaches. In addition, the results of this study will likely have broader applications in other types of pediatric and adult leukemia that are refractory to therapy.

Public Health Relevance

This study will have a large overall impact on the field of leukemia because it will fundamentally advance our mechanistic understanding of leukemogenesis and maintenance of leukemia-initiating cells. This project will enable the discovery of pharmacological inhibitors tested in patient pre-clinical mouse models that can control refractory and relapse leukemia, which are the major causes of death in cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Jhappan, Chamelli
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Baylor College of Medicine
Schools of Medicine
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Park, Chun Shik; Lacorazza, H Daniel (2018) Retroviral Transduction of Quiescent Murine Hematopoietic Stem Cells. Methods Mol Biol 1686:173-182
Lacorazza, H Daniel (2017) KLF4 represses MAP2K7 signaling in T-ALL. Oncotarget 8:73366-73367
Shen, Ye; Chen, Taylor J; Lacorazza, H Daniel (2017) Novel tumor-suppressor function of KLF4 in pediatric T-cell acute lymphoblastic leukemia. Exp Hematol 53:16-25