Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition.
King Pan NgAditi ManjeriKian Leong LeeWeijie HuangSoo Yong TanCharles T H ChuahLorenz PoellingerS Tiong OngPublished in: Blood (2014)
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.
Keyphrases
- chronic myeloid leukemia
- stem cells
- endothelial cells
- tyrosine kinase
- bone marrow
- gene expression
- oxidative stress
- genome wide
- cell cycle arrest
- epidermal growth factor receptor
- type diabetes
- induced apoptosis
- mesenchymal stem cells
- cell therapy
- endoplasmic reticulum stress
- metabolic syndrome
- radiation therapy
- squamous cell carcinoma
- drug delivery
- skeletal muscle
- helicobacter pylori infection
- cancer therapy
- rna seq
- peripheral blood
- single cell
- smoking cessation
- locally advanced
- atomic force microscopy