The molecular mechanism of the aberrant expression of the B-cell specific PAX5 gene in t(8;21) AML

Ray, Debleena (2013). The molecular mechanism of the aberrant expression of the B-cell specific PAX5 gene in t(8;21) AML. University of Birmingham. Ph.D.

Preview

Ray13PhD.pdf
PDF - Accepted Version
Download (4MB)

Abstract

B-cell specific gene PAX5 (Busslinger, 2004) is aberrantly expressed in t(8;21) AML (Tiacci et al., 2004) and is potentially involved in blocking myeloid differentiation. To understand the mechanism of PAX5 deregulation in t(8;21) AML we examined the expression, chromatin structure, histone modifications and RNA Polymerase II recruitment at PAX5 in t(8;21) AML, in non-t(8;21) myeloid precursors and in a pre-B-cell-line. Our studies show that in non t(8;21) myeloid precursors, the PAX5 gene is poised for transcription but is repressed by polycomb complexes. This polycomb repression is alleviated in t(8;21) cells leading to PAX5 expression. t(8;21) AML model Kasumi-1 carries an activating C-KIT mutation that leads to constitutive activation of different downstream signalling pathways (Larizza et al., 2005). Some of these signalling pathways have been shown to regulate association of polycomb complexes with chromatin (Voncken et al., 2005). Our study shows that small molecule mediated inhibition of constitutively activated JNK, MEK and P38 signalling in Kasumi-1 cells lead to a down regulation of PAX5 expression, decrease in elongating RNA Polymerase II and H327ac with concomitant increase in H3K27me3 at PAX5. This suggests that deregulated MAPkinase signalling in t(8;21) AML leads to the dissociation of polycomb complexes from PAX5 causing its activation. It also suggests a novel role of tyrosine kinase mutations in lineage specification and differentiation block in t(8;21) AML.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):