Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition.
C-abl oncogene 1, nonreceptor tyrosine kinase (ABL1) kinase inhibitors such as imatinib mesylate (imatinib) are effective in managing chronic myeloid leukemia (CML) but incapable of eliminating leukemia stem cells (LSCs), suggesting that kinase-independent pathways support LSC survival. Given that the bone marrow (BM) hypoxic microenvironment supports hematopoietic stem cells, we investigated whether hypoxia similarly contributes to LSC persistence. Importantly, we found that although breakpoint cluster region (BCR)-ABL1 kinase remained effectively inhibited by imatinib under hypoxia, apoptosis became partially suppressed. Furthermore, hypoxia enhanced the clonogenicity of CML cells, as well as their efficiency in repopulating immunodeficient mice, both in the presence and absence of imatinib. Hypoxia-inducible factor 1 α (HIF1-α), which is the master regulator of the hypoxia transcriptional response, is expressed in the BM specimens of CML individuals. In vitro, HIF1-α is stabilized during hypoxia, and its expression and transcriptional activity can be partially attenuated by concurrent imatinib treatment. Expression analysis demonstrates at the whole-transcriptome level that hypoxia and imatinib regulate distinct subsets of genes. Functionally, knockdown of HIF1-α abolished the enhanced clonogenicity during hypoxia. Taken together, our results suggest that in the hypoxic microenvironment, HIF1-α signaling supports LSC persistence independent of BCR-ABL1 kinase activity. Thus, targeting HIF1-α and its pathway components may be therapeutically important for the complete eradication of LSCs.
Cancer Science Institute of Singapore, National University of Singapore, Singapore;
King Pan
KP
Ng
Cancer and Stem Cell Biology Signature Research Program, Duke-National University of Singapore Graduate Medical School, Singapore;
Aditi
A
Manjeri
Cancer Science Institute of Singapore, National University of Singapore, Singapore;
Kian Leong
http://orcid.org/0000-0002-0443-2746
KL
Lee
Cancer and Stem Cell Biology Signature Research Program, Duke-National University of Singapore Graduate Medical School, Singapore;
Weijie
W
Huang
Department of Pathology and.
Soo Yong
SY
Tan
Cancer and Stem Cell Biology Signature Research Program, Duke-National University of Singapore Graduate Medical School, Singapore; Department of Haematology, Singapore General Hospital, Singapore;
Charles T H
CT
Chuah
Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden;
Lorenz
L
Poellinger
Cancer and Stem Cell Biology Signature Research Program, Duke-National University of Singapore Graduate Medical School, Singapore; Department of Haematology, Singapore General Hospital, Singapore; Department of Medical Oncology, National Cancer Centre, Singapore; and Department of Medicine, Duke University Medical Center, Durham, NC.
S Tiong
ST
Ong
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D015687:Cell Hypoxia; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D001549:Benzamides; D051793:Hypoxia-Inducible Factor 1; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D010100:Oxygen