Regulation of HIF-1α signaling and chemoresistance in acute lymphocytic leukemia under hypoxic conditions of the bone marrow microenvironment.
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.
Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, TX, USA.
Olga
O
Frolova
Ismael
I
Samudio
Juliana Maria
JM
Benito
Rodrigo
R
Jacamo
Steven M
SM
Kornblau
Ana
A
Markovic
Wendy
W
Schober
Hongbo
H
Lu
Yi Hua
YH
Qiu
Daniela
D
Buglio
Teresa
T
McQueen
Sherry
S
Pierce
Elizabeth
E
Shpall
Sergej
S
Konoplev
Deborah
D
Thomas
Hagop
H
Kantarjian
Richard
R
Lock
Michael
M
Andreeff
Marina
M
Konopleva
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007223:Infant; D008297:Male; D051379:Mice; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D055815:Young Adult
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose