Abstract
Abstract 1674
The t(9;22)(q34;q11) generating the Philadelphia chromosome and the BCR/ABL1 fusion gene represents the cytogenetic hallmark of chronic myeloid leukemia (CML). About 5–10% of CML cases show variant translocations with the involvement of other chromosomes in addition to chromosomes 9 and 22. The greater frequency of occurrence of genomic microdeletions proximally to ABL1 or distally to BCR has been reported in CML cases with variant translocations (30–40%) than in cases with a classic t(9;22) (10–18%). The prognostic significance of variant t(9;22) was unclear and debated in the pre-imatinib era, whereas recent studies of large CML series showed that the presence of variant translocations has no impact on the cytogenetic and molecular response or on prognosis (Marzocchi et al. Blood 2011,117:6793-800). However, the molecular bases of differences between CML patients with classic and variant t(9;22) have never been elucidated.
Here we report a gene expression profile analysis of 8 CML cases with variant t(9;22) and 12 patients with a classic t(9;22). RNA samples were extracted from bone marrow cells and hybridized on the Agilent SurePrint G3 Human GE 8×60K Microarray slide (Agilent Technologies). Ingenuity Pathways Analysis (IPA, www.ingenuity.com) software was used to provide an accurate biological and statistical analysis of microarray experimental data revealing functional relationships among the identified genes.
Gene expression analysis identified a 59 gene set able to distinguish the two CML subsets. These genes are mostly involved in the development of the hematological system and in the occurrence of hematological diseases. Forty-five out of 59 (76%) genes were up-regulated, causing the probable activation of different molecular mechanisms such as cellular responses to stimuli, protein degradation, DNA repair, cell cycle progression. IPA analysis revealed that most of the dysregulated genes are included in a network where they are functionally linked to MAPK p38, AKT, and NFKB. Moreover, several genes play a role in cytoskeleton organization (WIPF1), in signal transduction and cell cycle progression (TRIB1, PDE4B, PTK2B, PLK3), in regulation of apoptosis (ZFAND5, STK17B), and in protein degradation (ZFAND5, SNRPG). On the contrary, among the downregulated genes, 5 (BCDIN3D, TMEM68, HILPDA, TMEM68, and C17orf61) establish direct interactions with ubiquitin C (UBC), a crucial gene involved in different intracellular mechanisms such as protein degradation, DNA repair, cell cycle regulation, and the regulation of other signaling pathways.
In conclusion, gene expression profiling in cases with variant t(9;22) revealed biological differences in this CML subset. Our data show an overall deregulation of genes involved in hematological system development and in cell proliferation signaling pathway.
Disclosures:
No relevant conflicts of interest to declare.
Travels with ubiquitin: from protein degradation to DNA repair