{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T11:00:53Z","timestamp":1789210853231,"version":"build-2803163510"},"reference-count":30,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2011,12,2]],"date-time":"2011-12-02T00:00:00Z","timestamp":1322784000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2012,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND:<\/jats:title><jats:p>Patients with chronic myelogenous leukemia (CML) in blast crisis have a poor response to tyrosine kinase inhibitors designed to inhibit the breakpoint cluster region\u2013v\u2010Abelson murine leukemia viral oncogene homolog 1 (BCR\u2010ABL1) oncogene. Recent work has demonstrated that heme oxygenase 1 (HO\u20101) expression is increased in BCR\u2010ABL1\u2013expressing cells and that the inhibition of HO\u20101 in CML leads to reduced cellular growth, suggesting that HO\u20101 may be a plausible target for therapy. The objective of the current study was to clarify the mechanism of HO\u20101 overexpression and the role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase as a contributor to this mechanism in CML.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS:<\/jats:title><jats:p>HO\u20101 expression was evaluated in bone marrow specimens from patients with CML in various stages of disease, in a transplantation\u2010based model for CML, and in CML cell lines. Chemical and genetic inhibition of the NADPH oxidase was carried out in CML cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS:<\/jats:title><jats:p>Specimens from patients with CML in blast crisis displayed higher levels of HO\u20101 staining than specimens from patients with CML in chronic or accelerated phase. HO\u20101 up\u2010regulation in BCR\u2010ABL1\u2013expressing cells was suppressed by diphenyleneiodonium (DPI), a chemical inhibitor of the NADPH oxidase. Targeting the NADPH oxidase through RNA interference (RNAi) to Ras\u2010related C3 botulinum toxin substrate 1 (Rac1), a dominant\u2010negative Rac1 construct or an inhibitor of Rac1 activity also blunted HO\u20101 protein expression. Moreover, inhibition of the NADPH oxidase by RNAi directed toward the 47\u2010kd cytosolic subunit of Nox (p47phox) similarly abrogated HO\u20101 levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS:<\/jats:title><jats:p>BCR\u2010ABL1 expression up\u2010regulated HO\u20101, a survival factor for CML cells. This up\u2010regulation was more pronounced in blast crisis CML relative to early stage disease and was mediated by the NADPH oxidase components Rac1 and p47phox. The expression of p47phox was increased in BCR\u2010ABL1\u2013expressing cells. Cancer 2011. \u00a9 2011 American Cancer Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.26621","type":"journal-article","created":{"date-parts":[[2011,12,3]],"date-time":"2011-12-03T11:52:25Z","timestamp":1322913145000},"page":"3433-3445","source":"Crossref","is-referenced-by-count":26,"title":["Inhibition of the NADPH oxidase regulates heme oxygenase 1 expression in chronic myeloid leukemia"],"prefix":"10.1002","volume":"118","author":[{"given":"Melissa M.","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Irwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kechen","family":"Ban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph B.","family":"Arlinghaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hesham 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