Induction of tumor arrest and differentiation with prolonged survival by intermittent hypoxia in a mouse model of acute myeloid leukemia.
We showed previously that mild real hypoxia and hypoxia-mimetic agents induced in vitro cell differentiation of acute myeloid leukemia (AML). We here investigate the in vivo effects of intermittent hypoxia on syngenic grafts of leukemic blasts in a PML-RARalpha transgenic mouse model of AML. For intermittent hypoxia, leukemic mice were housed in a hypoxia chamber equivalent to an altitude of 6000 m for 18 hours every consecutive day. The results show that intermittent hypoxia significantly prolongs the survival of the leukemic mice that received transplants, although it fails to cure the disease. By histologic and cytologic analyses, intermittent hypoxia is shown to inhibit the infiltration of leukemic blasts in peripheral blood, bone marrow, spleen, and liver without apoptosis induction. More intriguingly, intermittent hypoxia also induces leukemic cells to undergo differentiation with progressive increase of hypoxia-inducible factor-1alpha protein, as evidenced by morphologic criteria of maturating myeloid cells and increased expression of mouse myeloid cell differentiation-related antigens Gr-1 and Mac-1. Taken together, this study represents the first attempt to characterize the in vivo effects of hypoxia on an AML mouse model. Additional investigations may uncover ways to mimic the differentiative effects of hypoxia in a manner that will benefit human patients with AML.
Liu
Wei
W
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education of China, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine.
Guo
Meng
M
Xu
Ya-Bei
YB
Li
Dao
D
Zhou
Zhao-Nian
ZN
Wu
Ying-Li
YL
Chen
Zhu
Z
Kogan
Scott C
SC
Chen
Guo-Qiang
GQ
D000818:Animals; D017209:Apoptosis; D001752:Blast Crisis; D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation; D015687:Cell Hypoxia; D003035:Cobalt / Q000494:pharmacology; D020544:Graft vs Leukemia Effect; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000401:mortality* / Q000517:prevention & control*; D008099:Liver / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D019707:Receptors, Chemokine / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D015996:Survival Rate; D014407:Tumor Cells, Cultured / Q000637:transplantation
C503133:Gr-1 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016177:Macrophage-1 Antigen; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D019707:Receptors, Chemokine; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D003035:Cobalt; C018021:cobaltous chloride