STANDARD_NAME	RAY_TARGETS_OF_P210_BCR_ABL_FUSION_DN
SYSTEMATIC_NAME	M319
COLLECTION	C2:CGP
MSIGDB_URL	https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/RAY_TARGETS_OF_P210_BCR_ABL_FUSION_DN
NAMESPACE	HUMAN_SEQ_ACCESSION
DESCRIPTION_BRIEF	Genes down-regulated in HL-60 cells (acute myeloid leukemia, AML) by expression of p210 BCR-ABL [GeneID=613;25] fusion protein.
DESCRIPTION_FULL	Chronic myelogenous leukemia (CML) results from a t(9,22) translocation, producing the p210(BCR-ABL) oncoprotein, a tyrosine kinase that causes transformation and chemotherapy resistance. To further understand mechanisms mediating chemotherapy resistance, we identified 556 differentially regulated genes in HL-60 cells stably expressing p210(BCR-ABL) versus those expressing an empty vector using cDNA macro- and oligonucleotide microarrays. These BCR-ABL-regulated gene products play diverse roles in cellular function including apoptosis, cell cycle regulation, intracellular signaling, transcription, and cellular adhesion. In particular, we identified up-regulation of the inducible form of heat shock protein 70 (Hsp70), and further explored the mechanism for its up-regulation. In HL-60/BCR-ABL and K562 cells (expressing p210(BCR-ABL)), abundant cytoplasmic Hsp70 expression was detected by immunoblot analysis. Moreover, cells isolated from bone marrow aspirates of patients in different stages of CML (chronic, aggressive, and blast crisis) express Hsp70. Expression of p210(BCR-ABL) in BCR-ABL negative cells induced transcription of the proximal Hsp70 promoter. Mutational analysis mapped the major p210(BCR-ABL) responsive element to a high affinity 5'(A/T)GATA(A/G)-3' GATA response element (GATA-RE) that binds GATA-1 in CML cells. The GATA-RE was sufficient to confer p210(BCR-ABL)- and p185(BCR-ABL)-mediated trans-activation to an inert promoter. Short interfering RNA mediated knockdown of Hsp70 expression in K562 cells induced marked sensitivity to paclitaxel-induced apoptosis. Together these findings indicate that BCR-ABL confers chemotherapeutic resistance through intracellular signaling to the GATA-RE element found in the promoter region of the anti-apoptotic Hsp70 protein. We suggest that down-regulation of the GATA-Hsp70 pathway may be useful in the treatment of chemotherapy-resistant CML.
PMID	15155749
GEOID	
AUTHORS	Ray S,Lu Y,Kaufmann SH,Gustafson WC,Karp JE,Boldogh I,Fields AP,Brasier AR
CONTRIBUTOR	Arthur Liberzon
CONTRIBUTOR_ORG	MSigDB Team
EXACT_SOURCE	Table 3
FILTERED_BY_SIMILARITY	
EXTERNAL_NAMES_FOR_SIMILAR_TERMS	
EXTERNAL_DETAILS_URL	
SOURCE_MEMBERS	AB009282,AF042378,AF044253,AI352450,J04131,L19182,M15024,M30818,M58597,M97287,U24152,U41303,X17042,X91809,X97267,Y14768
GENE_SYMBOLS	CYB5B,TUBGCP3,KCNAB2,,GGT1,IGFBP7,MYB,MX2,FUT4,SATB1,PAK1,SNRPN,SRGN,RGS19,PTPRCAP,AIF1
FOUNDER_NAMES