Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5.
Correct hematopoietic differentiation requires the tightly regulated execution of lineage-specific and stage-restricted gene expression programs. This process is disturbed in hematological malignancies that typically show incomplete differentiation but often also display a mixed lineage phenotype. Co-expression of lymphoid and myeloid molecules is a well-known feature of acute myeloblastic leukemia (AML) with t(8;21). These cells consistently express the B-cell-specific transcription factor PAX5, and the B-cell-specific cell surface protein CD19. However, the functional consequences of PAX5 expression are unknown. To address this question, we studied the chromatin features of CD19, which is a direct target of PAX5 in cells with and without the t(8;21) chromosomal translocation. We show that CD19 chromatin exists in a poised configuration in myeloid progenitors and that this poised chromatin structure facilitates PAX5-dependent CD19 activation. Our results also show a positive correlation between PAX5 and CD19 expression in t(8;21)-positive AML cells and demonstrate that PAX5 binds to the promoter and enhancer of CD19 gene and remodels chromatin structure at the promoter. This study shows that expression of PAX5 in leukemic cells has functional consequences and points to an important role of a progenitor-specific chromatin configuration in myeloid leukemia.
Walter
K
K
Section of Experimental Haematology, Leeds Institute of Molecular Medicine, St James's University Hospital, University of Leeds, Leeds, UK.
Cockerill
P N
PN
Barlow
R
R
Clarke
D
D
Hoogenkamp
M
M
Follows
G A
GA
Richards
S J
SJ
Cullen
M J
MJ
Bonifer
C
C
Tagoh
H
H
D018941:Antigens, CD19 / Q000235:genetics* / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002843:Chromatin / Q000737:chemistry* / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D018983:DNA Footprinting; D004742:Enhancer Elements, Genetic; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051757:PAX5 Transcription Factor / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014178:Translocation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
D018941:Antigens, CD19; D002843:Chromatin; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human