HIF-1α can act as a tumor suppressor gene in murine acute myeloid leukemia

TY - JOUR

T1 - HIF-1α can act as a tumor suppressor gene in murine acute myeloid leukemia

AU - Velasco-Hernandez, Talia

AU - Hyrenius-Wittsten, Axel

AU - Rehn, Matilda

AU - Bryder, David

AU - Cammenga, Jörg

N1 - © 2014 by The American Society of Hematology.

PY - 2014/12/4

Y1 - 2014/12/4

N2 - Self-renewal of hematopoietic stem cells (HSCs) and leukemia-initiating cells (LICs) has been proposed to be influenced by low oxygen tension (hypoxia). This signaling, related to the cellular localization inside the bone marrow niche and/or influenced by extrinsic factors, promotes the stabilization of hypoxia-inducible factors (HIFs). Whether HIF-1α can be used as a therapeutic target in the treatment of myeloid malignancies remains unknown. We have used 3 different murine models to investigate the role of HIF-1α in acute myeloid leukemia (AML) initiation/progression and self-renewal of LICs. Unexpectedly, we failed to observe a delay or prevention of disease development from hematopoietic cells lacking Hif-1α. In contrast, deletion of Hif-1α resulted in faster development of the disease and an enhanced leukemia phenotype in some of the investigated models. Our results therefore warrant reconsideration of the role of HIF-1α and, as a consequence, question its generic therapeutic usefulness in AML.

AB - Self-renewal of hematopoietic stem cells (HSCs) and leukemia-initiating cells (LICs) has been proposed to be influenced by low oxygen tension (hypoxia). This signaling, related to the cellular localization inside the bone marrow niche and/or influenced by extrinsic factors, promotes the stabilization of hypoxia-inducible factors (HIFs). Whether HIF-1α can be used as a therapeutic target in the treatment of myeloid malignancies remains unknown. We have used 3 different murine models to investigate the role of HIF-1α in acute myeloid leukemia (AML) initiation/progression and self-renewal of LICs. Unexpectedly, we failed to observe a delay or prevention of disease development from hematopoietic cells lacking Hif-1α. In contrast, deletion of Hif-1α resulted in faster development of the disease and an enhanced leukemia phenotype in some of the investigated models. Our results therefore warrant reconsideration of the role of HIF-1α and, as a consequence, question its generic therapeutic usefulness in AML.

KW - Animals

KW - Gene Deletion

KW - Genes, Tumor Suppressor

KW - Hematopoietic Stem Cells/metabolism

KW - Hypoxia-Inducible Factor 1, alpha Subunit/genetics

KW - Leukemia, Myeloid, Acute/genetics

KW - Mice

KW - Mice, Transgenic

KW - Neoplasms, Experimental/genetics

KW - Tumor Suppressor Proteins/genetics

U2 - 10.1182/blood-2014-04-567065

DO - 10.1182/blood-2014-04-567065

M3 - Journal article

C2 - 25267197

SN - 0006-4971

VL - 124

SP - 3597

EP - 3607

JO - Blood

JF - Blood

IS - 24

ER -