Authors: Olga Frolova, Ismael Samudio, Juliana Maria Benito, Rodrigo Jacamo, Steven M. Kornblau, Ana Markovic, Wendy Schober, Hongbo Lu, Yi Hua Qiu, Daniela Buglio, Teresa McQueen, Sherry Pierce, Elizabeth J. Shpall, Sergej Konoplev, Deborah Thomas, Hagop Kantarjian, Richard Lock, Michael Andreeff and Marina Konopleva
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Ismael Samudio
Ponitificia Universidad Javeriana; Bogota, Colombia
Juliana Maria Benito
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Rodrigo Jacamo
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Steven M. Kornblau
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Department of Lymphoma/Myeloma; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Ana Markovic
Department of Stem Cell Transplantation and Cellular Therapy; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Wendy Schober
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Hongbo Lu
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Yi Hua Qiu
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Daniela Buglio
Department of Lymphoma/Myeloma; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Teresa McQueen
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Sherry Pierce
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Elizabeth J. Shpall
Department of Stem Cell Transplantation and Cellular Therapy; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Sergej Konoplev
Department of Hematopathology; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Deborah Thomas
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Hagop Kantarjian
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Richard Lock
Department of Stem Cell Transplantation and Cellular Therapy; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Michael Andreeff
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Department of Stem Cell Transplantation and Cellular Therapy; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Marina Konopleva
Corresponding author: mkonople@mdanderson.org
Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Department of Stem Cell Transplantation and Cellular Therapy; The University of Texas MD Anderson Cancer Center; Houston, TX USA
Abstract:
Overcoming resistance to chemotherapy is the main therapeutic challenge in the treatment of acute lymphocytic leukemia (ALL). Interactions between leukemia cells and the microenvironment promote leukemia cell survival and confer resistance to chemotherapy. Hypoxia is an integral component of bone marrow (BM) microenvironment. Hypoxia-inducible factor-1α (HIF-1), a key regulator of the cellular response to hypoxia, regulates cell growth and metabolic adaptation to hypoxia. HIF-1α expression, analyzed by Reverse Phase Protein Arrays in 92 specimens from newly diagnosed patients with pre-B-ALL, had a negative prognostic impact on survival (p = 0.0025). Inhibition of HIF-1α expression by locked mRNA antagonist (LNA) promoted chemosensitivity under hypoxic conditions, while pharmacological or genetic stabilization of HIF-1α under normoxia inhibited cell growth and reduced apoptosis induction by chemotherapeutic agents. Co-culture of pre-B ALL or REH cells with BM-derived mesenchymal stem cells (MSC) under hypoxia resulted in further induction of HIF-1α protein and acquisition of the glycolytic phenotype, in part via stroma-induced AKT/mTOR signaling. mTOR blockade with everolimus reduced HIF-1α expression, diminished glucose uptake and glycolytic rate and partially restored the chemosensitivity of ALL cells under hypoxia/stroma co-cultures. Hence, mTOR inhibition or blockade of HIF-1α-mediated signaling may play an important role in chemosensitization of ALL cells under hypoxic conditions of the BM microenvironment.
Received: December 19, 2011; Accepted: May 22, 2012
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