Proteomics of Acute Myeloid Leukemia [thesis]

Mumtaz Yaseen
Acute Myeloid Leukemia (AML) is characterized by specific cytogenetic aberrations that are strong determinants of prognostic outcome and therapeutic response. Because the pathological outcome of AML patients with cytogentic abnormalities differs considerably we hypothesized that their proteome may also differ specifically in their expression pattern, protein interaction pathways and posttranslational modifications. We performed this study using 42 AML patients diagnosed for various cytogenetic
more » ... arious cytogenetic abnormalities based on two-dimensional gel electrophoresis and MALDI TOF Tandem MS (MS/MS) analysis. We could identify significant differences in the proteome and posttranslational modifications of peptides, later confirmed by other methods, between cytogenetic groups. The interactome analysis based on computational bioinformatics reveals a major regulating networks, MAPK8 and MYC for complex aberrant karyotype, TP53 for t(8;21), TP53- MYC- PRKAC for 11q23, JUN and MYC for Inv(16). We could show in our validation and characterisation experiments that survivin is a novel target of t(8;21) leukemia and AML1-ETO directly regulates its expression to induce the differentiation block that could be overcome by silencing its expression. Further, we analysed 42 MS spectra representative of hnRNPH1, Calreticulin and hnRNPA2/B1 in a peak explorer which reveals a cytogenetic specific posttranslational modification of β-O-linked N-acetyl glucosamine (O-GlcNAc) of hnRNPH1 in AML patients with 11q23 translocation, an acetylation of calreticulin in t(8;21) translocation and methylation of hnRNPA2/B1 in patients with translocations of t(8;21) and inv(16). This report may lead to a new thinking about the AML pathogenesis as differences at PTM level could be used to distinguish different subtypes of AML besides for testing the therapeutic significance. Further, we characterised the biological role of survivin identified specifically from t(8;21) patients. We could show that AML1-ETO induces the expression of survivin both in a cell line model [...]
doi:10.5282/edoc.6988 fatcat:mpq7qes4tratvlgnunwvxnj3tu