Identification of novel molecular targets for early detection, treatment, and monitoring of leukemia and lymphoma within the Hispanic population
Leukemia. In the United States, nearly 146,250 new cases of blood cancers are expected to be diagnosed in 2020 . Leukemia, a form of cancer that affects white blood cells found in the bone marrow and blood, will account for approximately 60,530 of these cases and will be responsible for 23,100 deaths. Of these new diagnoses, 21,040 will be classified as chronic lymphocytic leukemia (CLL), 8,450 chronic myelogenous leukemia (CML), 19,940 will be acute myelogenous leukemia (A.M.L.), and 6,150 will be acute lymphocytic leukemia (ALL) . While there has been an improvement in the survival rates for some of these cancers, they are NOT distributed equally among racial and ethnic groups. Hispanics often fail to demonstrate any positive statistical change due to newly developed therapies. Race and ethnicity remain a significant barrier to good clinical care for cancers such as ALL. Despite an approximate 85% cure rate, ALL remains the second most common cause of cancer-related mortality in children in the U.S. . Unfortunately, Hispanic children have an increased incidence of ALL [4, 5] higher rates of relapse and among the poorest outcomes [6-10], a well-known and significant cancer health disparity that must be addressed.
The Paso del Norte Region. The El Paso-Juarez Borderplex has a population of approximately 2.5 million residents, with 840,758 residents located on the U.S. side of the border . More than 82% of El Paso County, TX residents are Hispanic , 96% of Mexican origin [12-14]. Not surprisingly, age-adjusted ALL incidence rates for El Paso county were higher compared to regions of Texas not highly populated by Hispanics between 2000-2016 . It is a well-known fact that Hispanic communities experience disproportionate health outcomes regardless of equal care . In fact, current therapeutic strategies lead to a refractory or relapse response in this population. Compounding these obstacles is the lack of participation or inclusion of minorities in clinical trials and cancer research . Alarmingly, less than 2% of genome-wide studies are from Hispanic samples. Therefore, there is a pressing need to study oncogenic drivers within this disproportionately affected population.
Cancer is the second leading cause of death in the United States and the primary cause of death for Hispanic Americans as first reported in 2012 [1, 18]. “Health disparities” contribute to cancer initiation, development, incidence, prevalence, and severity. The National Cancer Institute (NCI) defines cancer health disparities as “adverse differences in cancer incidence, prevalence, death, survivorship, and burden of cancer or related health conditions that exist among specific population groups in the United States .” A key population characteristic is defined by race and ethnicity, and cancer exerts a marked detrimental effect on the Hispanic demographic. While socioeconomic status (income, education, access to health care), geographic location, culture, sex, early detection, and treatment services are important cancer risk factors, genetic drivers associated with race and ethnicity play an equally influential role in cancer health disparities such as leukemia. Importantly, advances in targeted therapies now allow physicians to personalize treatment strategies based on an individual’s genetic content.
Dr. Robert A. Kirken (Principal Investigator), is the Dean of the College of Science at the University of Texas at El Paso (UTEP) and has served as the Program Director of the NIH-NCRR-RCMI Sponsored Border Biomedical Research Center (BBRC) for 10 years.
Dr. Georgialina Rodriguez (Co-Investigator), is an Associate Professor of Research within the Department of Biological Sciences at UTEP and is a faculty member of the BBRC. Dr. Rodriguez is a cancer biologist and immunologist with experience investigating the molecular mechanisms that drive kinase-mediated diseases such as leukemia. Her work focuses on better understanding phospho-regulation of Jak proteins in order to generate small molecule inhibitors which more selectively target oncogenic kinases, like Jak3, in contrast to the current pan-kinase inhibitors available.
Dr. Chuan Xiao (Co-Investigator), is an Associate Professor of the Department of Chemistry at UTEP. Dr. Xiao is a structural biochemist, with interests in virology, chronobiology, cancer, and plants. He combines X-ray crystallography, cryogenic electron microscopy, and other bioinformatics, biophysical, and biochemical tools to study the structures of biological complexes and analyze their functions.
Dr. Lin Li (Co-Investigator), is an Assistant Professor of the Department of Physics at UTEP. Dr. Li's research interests focus on Computational Biophysics, and his main research goals are to:
1) develop state-of-the-art software packages for modeling and simulation of disease-related biological systems and 2) use computational approaches to study disease-related biological systems. He has additional interests in bioinformatics, protein interactions, viral capsid assembly, and molecular motors.
BBRC support has resulted in the publication of “The Genomic Landscape of a Restricted ALL Cohort from Patients Residing on the U.S./Mexico Border” and “The Many Faces of J.A.K.s and STATs within the COVID-19 storm.” and the following publications in scientific journals.
- Grant, A.H., Rodriguez, G., Rodriguez, A.C., Morán-Santibañez, Aleksander Lazarski, K., Mohl, J.E., Leung, M-Y., and Kirken, R.A. JAK1 JH2 mutation V666G found in Acute Lymphoblastic Leukemia shows dominance by impairing JAK3 phosphorylation in IL-2 signaling. Manuscript in Preparation.
- Martinez, G.S., Rodriguez, G., Negrete, O.D., Ross, J.A., and Kirken, R.A. Identification and characterization of autophosphorylated Y841 within Janus Tyrosine Kinase 3 is required for activation of STAT5B and positionally conserved within J.A.K. and other kinase family members. Manuscript in Preparation.
- Grant AH, Ayala-Marin YM, Mohl JE, Robles-Escajeda E, Rodriguez G, Dutil J, Kirken RA. The Genomic Landscape of a Restricted ALL Cohort from Patients Residing on the U.S./Mexico Border. Int J Environ Res Public Health. 2021 Jul 9;18(14):7345.
- Grant, A.H., Estrada, A., Ayala, Y.M., Alvidrez-Camacho, A.Y., Rodriguez, G., Robles, E., Cadena, D.A. Rodriguez, A.C. and Kirken, R.A. The Many Faces of J.A.K.s and STATs within the COVID-19 storm. Front. Immunl., 13 July 2021; 12:690477.
- Ayala-Marin, Y.M.; Grant, A.H.; Rodriguez, G.; Kirken, R.A. Quadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation. Int. J. Mol. Sci. 2021, 22, x. https://doi.org/10.3390/xxxxx
- Estrada A 3rd, Rodriguez A.C., Rodriguez G, Grant A.H., Ayala-Marin Y.M., Arrieta AJ, Kirken RA. Phosphorylation of CrkL S114 induced by common gamma chain cytokines and T-cell receptor signal transduction. Sci Rep. 2021 Aug 20;11(1):16951. DOI: 10.1038/s41598-021-96428-y. PMID: 34417497; PMCID: PMC8379229.
Symposium Abstract Presentations by undergraduate students related to the project’s research:
- Alvidrez-Camacho, A.Y., Rodriguez, G., Bencomo, C., Kirken, R.A. Establishing a Mechanism of Tumor Evasion Through Adenosine Receptor Cross-talk with Common Gamma Chain Signing in Immune Cells. Fall 2021, American Society for Microbiology/Annual Biomedical Research Conference for Minority Students.
- Alvidrez-Camacho, A.Y., Rodriguez, G., Bencomo, C., Kirken, R.A. Regulation of Common Gamma Chain and JAK3 Pathway Signaling by Adenosine Receptor Cross-talk. Fall 2021, 2021 Gulf Coast Undergraduate Research Symposium.
- Mohl, J.E., Wang, B., and Leung, M-Y. OncoMiner: an updated pipeline for analyzing genomic sequencing data from changing. Fall 2021, Computational Approaches for Cancer Workshop of SC21 (Supercomputing Conference 2021).
- Damian K., Ayala-Marin, Y.M., Rodriguez, G., Kirken, R.A. Elucidation of Tyrosine Phosphorylation Sites within IL2-Ryc Using Customized Phospho-Specific Antibodies. Spring 2021, Couri Symposium, El Paso, Texas.
- Damian, K., Ayala-Marin, Y.M., Rodriguez, G., Kirken, R.A. Elucidation of Tyrosine Phosphorylation Sites within IL2-Ryc Using Customized Phospho-Specific Antibodies. Spring 2019, Couri Symposium, El Paso, Texas.
- American Cancer Society. 2020. Cancer Facts & Figures 2020. Cancer.org
- Rebecca L. Siegel, Kimberly D. Miller, Ahmedin Jemal. Cancer Statistics, 2020. CA: A Cancer Journal for Clinicians.70:1, 7-30.
- Pui, C.H. and S. Jeha, New therapeutic strategies for the treatment of acute lymphoblastic leukemia. Nature reviews. Drug discovery, 2007. 6(2): p. 149-65.
- Wilkinson, J.D., et al., Cancer incidence among Hispanic children in the United States. Rev Panam Salud Publica, 2005. 18(1): p. 5-13.
- Howe, H.L., et al., Annual report to the nation on the status of cancer, 1975-2003, featuring cancer among U.S. Hispanic/Latino populations. Cancer, 2006. 107(8): p. 1711-42.
- Carroll, W.L., Race, and outcome in childhood acute lymphoblastic leukemia. JAMA, 2003. 290(15): p. 2061-3.
- Kadan-Lottick, N.S., et al., Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia. JAMA, 2003. 290(15): p. 2008-14.
- Bhatia, S., et al., Racial and ethnic differences in survival of children with acute lymphoblastic leukemia. Blood, 2002. 100(6): p. 1957-64.
- Hord, M.H., et al., Ethnicity and cure rates of Texas children with acute lymphoid leukemia. Cancer, 1996. 77(3): p. 563-9.
- Kang, H., et al., Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia. Blood, 2010. 115(7): p. 1394-405.
- Bureau, U.S.C. Quick Facts 2018. V2018; Available from: https://www.census.gov/quickfacts/fact/table/US/PST045217#PST045217.https://www.census.gov/quickfacts/fact/table/US/PST045217#PST045217
- Center, P.R. Hispanic Trends, 2017. 2017; Available from www.pewhispanic.org
- Center, P.R., Hispanic/Latino Demographics.
- Flores, A. How the U.S. Hispanic population is changing. 2017 [cited 2018; Available from: http://www.pewresearch.org/fact-tank/2017/09/18/how-the-u-s-hispanic-population-is-changing/.
- Texas Cancer Registry. Age-Adjusted Invasive Cancer Incidence Rates in Texas Acute Lymphocytic Leukemia, 2000-2016. Cancer Incidence File, Jan 2019. Accessed Feb. 19, 2020. Available from: https://www.dshs.texas.gov/tcr/
- Bhatia, R. and H.J. Deeg, Treatment-related myelodysplastic syndrome: molecular characteristics and therapy. Curr Opin Hematol, 2011. 18(2): p. 77-82.
- Simon, M.A., et al., Improving diversity in cancer research trials: the story of the Cancer Disparities Research Network. Journal of cancer education: the official journal of the American Association for Cancer Education, 2014. 29(2): p. 366-74.
- American Cancer Society. Cancer Facts and Figures for Hispanics/ Latinos 2015-2017. 2015.
- National Cancer Institute. Cancer Disparities. 2018; Available from: https://www.cancer.gov/about-cancer/understanding/disparities?redirect=true.