Identification of heme oxygenase-1 as a novel BCR/ABL-dependent survival factor in chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is a stem cell disease in which BCR/ABL promotes the survival of leukemic cells. Heme oxygenase-1 (HO-1) is an inducible stress protein that catalyzes the degradation of heme and has recently been implicated in the regulation of growth and survival of various neoplastic cells. In the present study, we analyzed the expression and role of HO-1 in CML cells. As assessed by Northern and Western blot analysis as well as immunostaining, primary CML cells were found to express HO-1 mRNA and the HO-1 protein in a constitutive manner. Exposure of these cells to the BCR/ABL tyrosine kinase inhibitor STI571 resulted in decreased expression of HO-1 mRNA and protein. In addition, BCR/ABL was found to up-regulate HO-1 promoter activity, mRNA levels, and protein levels in Ba/F3 cells. To investigate the role of HO-1 for survival of primary CML cells, the HO-1 inducer hemin was used. Hemin-induced expression of HO-1 was found to protect CML cells from STI571-induced cell death. In addition, inhibition of HO-1 by zinc-(II)-deuteroporphyrin-IX-2,4-bisethyleneglycol resulted in a substantial decrease of cell viability. Furthermore, overexpression of HO-1 in the CML-derived cell line K562 was found to counteract STI571-induced apoptosis. Together, our data identify HO-1 as a novel BCR/ABL-driven survival molecule and potential target in leukemic cells in patients with CML. The pathogenetic and clinical implications of this observation remain to be elucidated.
Mayerhofer
Matthias
M
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
Florian
Stefan
S
Krauth
Maria-Theresa
MT
Aichberger
Karl J
KJ
Bilban
Martin
M
Marculescu
Rodrig
R
Printz
Dieter
D
Fritsch
Gerhard
G
Wagner
Oswald
O
Selzer
Edgar
E
Sperr
Wolfgang R
WR
Valent
Peter
P
Sillaber
Christian
C
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001549:Benzamides; D001664:Biliverdine / Q000378:metabolism / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology; D002461:Cell Line, Transformed; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051547:Heme Oxygenase-1; D006801:Humans; D000068877:Imatinib Mesylate; D007501:Iron / Q000378:metabolism / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation
D001549:Benzamides; D008565:Membrane Proteins; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D002248:Carbon Monoxide; D000068877:Imatinib Mesylate; D007501:Iron; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D016044:Fusion Proteins, bcr-abl; D001664:Biliverdine