Philadelphia chromosome-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL) is a malignancy of precursor B-lymphocytes with a high risk for relapse and poor overall survival for which better therapies are needed. Inactivating mutations in the Ikaros (IKZF1) gene encoding lymphoid transcription factors in ~85% of Ph+ B-ALL suggest its tumor-suppressor role in the pathogenesis of B-ALL. The poor prognosis of Ikaros- mutant B-ALL holds true irrespective of the Ph-chromosome status indicating that Ikaros mutations are directly responsible for resistance to chemotherapy. However, the biological role of Ikaros in the pathogenesis and therapy of B-ALL is not understood and is the focus of our current investigation. In the first Aim, an Ikzf1 conditional mouse model will be used to delineate the rol of Ikaros-inactivating mutations in the pathogenesis and poor response to treatment of B-ALL. Preliminary studies have shown that an aberrant increase in integrin signaling and activation of focal adhesion kinase (FAK) in Ikzf1-deficient B-ALL supports stromal-mediated growth and survival, and causes stromal-dependent resistance to BCR-ABL1 tyrosine kinase inhibitors such as dasatinib. Whether inhibition of FAK in Ikaros-mutant B-ALL interferes with leukemic cell survival and restores sensitivity to BCR-ABL1 inhibitors will be tested. Subsequently, a global approach will be taken to examine the signaling and transcriptional networks regulated by Ikaros during B cell precursor differentiation and determine which of these contribute to the precursor B-cell leukemic phenotype. This should identify additional potential drug targets, both downstream of and parallel to the FAK-mediated survival pathway. Finally, Ikzf1-deficient B- ALL appears to be highly resistant to glucocorticoids (GC), and the mechanism thereof will be investigated with the goal of identifying key nodes in the GC resistance pathway that can be exploited for combination therapy of B-ALL. In the second Aim, the knowledge gained from studies in the mouse models of B-ALL will be translated to human B-ALL. Samples from human patients with Ph+ B-ALL will be screened for IKZF1 mutations and propagated in immunodeficient (NSG) mice to expand the leukemic clone and generate leukemic mice for therapeutic studies. The response of human B-ALL to FAK inhibitors either alone or in combination with BCR- ABL1 inhibitors will be tested in vitro and in vivo. IKZF1-deficient Ph+ or Ph- B-ALL samples will also evaluated for activation of signaling and transcriptional pathways identified in Ikzf1-deficient mouse B-ALL. The strong similarities in the properties of mouse and human Ikaros-deficient B-ALL characterized to date suggest that this approach will identify additional druggable targets that are required for the survival and proliferation of therapy- resistant, high-risk human B-ALL. Together, the studies proposed in this application will provide critical new knowledge about the pathogenesis of Ikaros-mutant B-ALL, and set the stage for clinical studies using FAK in novel combination therapies to combat this disease.

Public Health Relevance

B-cell acute lymphoblastic leukemia (B-ALL) is a cancer of immune cells that has a high risk for relapse and poor overall survival. Mutations in a gene known as Ikaros have been shown to cause resistance to chemotherapy drugs in both human B-ALL and in mouse models of the disease. Our studies are aimed at understanding the biological role of Ikaros in the development of B-ALL and its response to therapy. By studying Ikaros-deficient B-ALL in mice, we have identified a novel pathway that may point the way to improved treatments and possible cure of this this devastating human leukemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA190964-04
Application #
9380323
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Duglas Tabor, Yvonne
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Hu, Yeguang; Yoshida, Toshimi; Georgopoulos, Katia (2017) Transcriptional circuits in B cell transformation. Curr Opin Hematol 24:345-352
Georgopoulos, Katia (2017) The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma. Genes Dev 31:439-450
Georgopoulos, Katia (2017) In search of the mechanism that shapes the neutrophil's nucleus. Genes Dev 31:85-87
Hu, Yeguang; Zhang, Zhihong; Kashiwagi, Mariko et al. (2016) Superenhancer reprogramming drives a B-cell-epithelial transition and high-risk leukemia. Genes Dev 30:1971-90