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Restoration of C/EBPalpha expression in a BCR-ABL+ cell line induces terminal granulocytic differentiation.
J Biol Chem 2003; 278(52):52651-9JB

Abstract

The transcription factor C/EBPalpha plays a critical role in the process of granulocytic differentiation. Recently, mutations that abrogated transcriptional activation of C/EBPalpha were detected in acute myeloid leukemia patient samples. Moreover, the progression of chronic myelogenous leukemia (CML) to blast crisis in patients was correlated with down-modulation of C/EBPalpha. The KCL22 cell line, derived from BCR-ABL+ CML in blast crisis, expressed wild-type C/EBPepsilon protein but not a functional C/EBPalpha, -beta, and -gamma. Restoration of C/EBPalpha expression in KCL22 cells triggered a profound proliferative arrest, a block in the G2/M phase of the cell cycle and a gradual increase in apoptosis. Within 3 days of inducing expression of C/EBPalpha, a remarkable neutrophilic differentiation of the KCL22 blast cells occurred as shown by morphologic changes, induction of expression of CD11b, primary, secondary, and tertiary granule proteins, and granulocyte colony-stimulating factor receptor. Using high density oligonucleotide microarrays, the gene expression profile of KCL22 cells stably transfected with C/EBPalpha was compared with that of empty vector, and we identified genes not previously known to be regulated by C/EBPalpha. These included the up-regulation of those genes important for regulation of hematopoietic stem cell homing, granulocytic differentiation, and cell cycle, whereas down-regulation occurred for genes coding for signaling molecules and transcription factors that are implicated in regulation of proliferation and differentiation of hematopoietic cells. Our study showed that restoration of C/EBPalpha expression in BCR-ABL+ leukemic cells in blast crisis is sufficient for rapid neutrophil differentiation suggesting a potential therapeutic role for ectopic transfer of C/EBPalpha in acute phase of CML.

Authors+Show Affiliations

Division of Hematology Oncology, Cedars-Sinai Medical Center, School of Medicine, UCLA, Los Angeles, California 90048, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14517214

Citation

Tavor, Sigal, et al. "Restoration of C/EBPalpha Expression in a BCR-ABL+ Cell Line Induces Terminal Granulocytic Differentiation." The Journal of Biological Chemistry, vol. 278, no. 52, 2003, pp. 52651-9.
Tavor S, Park DJ, Gery S, et al. Restoration of C/EBPalpha expression in a BCR-ABL+ cell line induces terminal granulocytic differentiation. J Biol Chem. 2003;278(52):52651-9.
Tavor, S., Park, D. J., Gery, S., Vuong, P. T., Gombart, A. F., & Koeffler, H. P. (2003). Restoration of C/EBPalpha expression in a BCR-ABL+ cell line induces terminal granulocytic differentiation. The Journal of Biological Chemistry, 278(52), pp. 52651-9.
Tavor S, et al. Restoration of C/EBPalpha Expression in a BCR-ABL+ Cell Line Induces Terminal Granulocytic Differentiation. J Biol Chem. 2003 Dec 26;278(52):52651-9. PubMed PMID: 14517214.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Restoration of C/EBPalpha expression in a BCR-ABL+ cell line induces terminal granulocytic differentiation. AU - Tavor,Sigal, AU - Park,Dorothy J, AU - Gery,Sigal, AU - Vuong,Peter T, AU - Gombart,Adrian F, AU - Koeffler,H Phillip, Y1 - 2003/09/29/ PY - 2003/10/1/pubmed PY - 2004/2/11/medline PY - 2003/10/1/entrez SP - 52651 EP - 9 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 278 IS - 52 N2 - The transcription factor C/EBPalpha plays a critical role in the process of granulocytic differentiation. Recently, mutations that abrogated transcriptional activation of C/EBPalpha were detected in acute myeloid leukemia patient samples. Moreover, the progression of chronic myelogenous leukemia (CML) to blast crisis in patients was correlated with down-modulation of C/EBPalpha. The KCL22 cell line, derived from BCR-ABL+ CML in blast crisis, expressed wild-type C/EBPepsilon protein but not a functional C/EBPalpha, -beta, and -gamma. Restoration of C/EBPalpha expression in KCL22 cells triggered a profound proliferative arrest, a block in the G2/M phase of the cell cycle and a gradual increase in apoptosis. Within 3 days of inducing expression of C/EBPalpha, a remarkable neutrophilic differentiation of the KCL22 blast cells occurred as shown by morphologic changes, induction of expression of CD11b, primary, secondary, and tertiary granule proteins, and granulocyte colony-stimulating factor receptor. Using high density oligonucleotide microarrays, the gene expression profile of KCL22 cells stably transfected with C/EBPalpha was compared with that of empty vector, and we identified genes not previously known to be regulated by C/EBPalpha. These included the up-regulation of those genes important for regulation of hematopoietic stem cell homing, granulocytic differentiation, and cell cycle, whereas down-regulation occurred for genes coding for signaling molecules and transcription factors that are implicated in regulation of proliferation and differentiation of hematopoietic cells. Our study showed that restoration of C/EBPalpha expression in BCR-ABL+ leukemic cells in blast crisis is sufficient for rapid neutrophil differentiation suggesting a potential therapeutic role for ectopic transfer of C/EBPalpha in acute phase of CML. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/14517214/Restoration_of_C/EBPalpha_expression_in_a_BCR_ABL+_cell_line_induces_terminal_granulocytic_differentiation_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=14517214 DB - PRIME DP - Unbound Medicine ER -