Transcriptomics

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Physiologic Hypoxia Promotes Maintenance of CML Stem Cells Despite Effective BCR−ABL1 Inhibition


ABSTRACT: ABL1 kinase inhibitors such as imatinib mesylate (IM) are effective in managing chronic myelogenous leukemia (CML) but incapable of eliminating leukemia stem cells (LSCs), suggesting that kinase−independent pathways support LSC survival. Given that the bone marrow hypoxic microenvironment supports hematopoietic stem cells, we investigated if hypoxia similarly contributes to LSC persistence. Importantly, we found that while BCR−ABL1 kinase remained effectively inhibited by IM 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 IM. HIF1−α, which is the master regulator of the hypoxia transcriptional response is expressed in the bone marrow specimens of CML individuals. In vitro, HIF1−α is stabilized during hypoxia and its expression and transcriptional activity can be partially attenuated by concurrent IM treatment. Expression analysis demonstrates at the whole transcriptome level that hypoxia and IM 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 independently of BCR−ABL1 kinase activity. Thus targeting HIF1−α and its pathway components may be therapeutically important for the complete eradication of LSCs. 24 samples consisting CD34+ bone marrow aspirates of 3 chronic phase patients that were subjected to 24h or 96h of DMSO/Normoxia (21% oxygen, 5% carbon dioxide) control, 2 µM Imatinib, hypoxia (0.5% oxygen, 5% carbon dioxide) or combined Imatinib/hypoxia treatments in triplicate cultures.

ORGANISM(S): Homo sapiens  

SUBMITTER: King Pan Ng   Weijie Huang  Kian Leong Lee  Kian Leong LEE  Charles T Chuah  Soo Yong Tan  Lorenz Poellinger  Sin Tiong Ong  Aditi Manjeri 

PROVIDER: E-GEOD-48294 | ArrayExpress | 2014-06-03

SECONDARY ACCESSION(S): GSE48294PRJNA209627

REPOSITORIES: GEO, ArrayExpress

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Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition.

Ng King Pan KP   Manjeri Aditi A   Lee Kian Leong KL   Huang Weijie W   Tan Soo Yong SY   Chuah Charles T H CT   Poellinger Lorenz L   Ong S Tiong ST  

Blood 20140404 21


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  ...[more]

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