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

Publication ,  Conference
Ng, KP; Manjeri, A; Lee, KL; Huang, W; Tan, SY; Chuah, CTH; Poellinger, L; Ong, ST
Published in: Blood
May 22, 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.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

May 22, 2014

Volume

123

Issue

21

Start / End Page

3316 / 3326

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Pyrimidines
  • Protein Kinase Inhibitors
  • Piperazines
  • Oxygen
  • Neoplastic Stem Cells
  • Mice, SCID
  • Mice
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Immunology
 

Citation

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MLA
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Ng, K. P., Manjeri, A., Lee, K. L., Huang, W., Tan, S. Y., Chuah, C. T. H., … Ong, S. T. (2014). Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition. In Blood (Vol. 123, pp. 3316–3326). United States. https://doi.org/10.1182/blood-2013-07-511907
Ng, King Pan, Aditi Manjeri, Kian Leong Lee, Weijie Huang, Soo Yong Tan, Charles T. H. Chuah, Lorenz Poellinger, and S Tiong Ong. “Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition.” In Blood, 123:3316–26, 2014. https://doi.org/10.1182/blood-2013-07-511907.
Ng KP, Manjeri A, Lee KL, Huang W, Tan SY, Chuah CTH, et al. Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition. In: Blood. 2014. p. 3316–26.
Ng, King Pan, et al. “Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition.Blood, vol. 123, no. 21, 2014, pp. 3316–26. Pubmed, doi:10.1182/blood-2013-07-511907.
Ng KP, Manjeri A, Lee KL, Huang W, Tan SY, Chuah CTH, Poellinger L, Ong ST. Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition. Blood. 2014. p. 3316–3326.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

May 22, 2014

Volume

123

Issue

21

Start / End Page

3316 / 3326

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Pyrimidines
  • Protein Kinase Inhibitors
  • Piperazines
  • Oxygen
  • Neoplastic Stem Cells
  • Mice, SCID
  • Mice
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Immunology