Identification and Analysis of Oncogenic Pathways in Deletion 20q Acute Myeloid Leukaemia
Abstract 1324 Deletion of the long arm of chromosome 20 [del(20q)] is a common recurrent chromosomal abnormality in acute myeloid leukaemia (AML). It is a key step in AML development and a better understanding of the associated molecular events is important. The abnormal chromosome 20 in del(20q) AM...
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| Published in: | Blood 2012-11, Vol.120 (21), p.1324-1324 |
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| Main Authors: | , , , , , |
| Format: | Article |
| Language: | eng |
| Online Access: | Get full text |
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| Summary: | Abstract 1324
Deletion of the long arm of chromosome 20 [del(20q)] is a common recurrent chromosomal abnormality in acute myeloid leukaemia (AML). It is a key step in AML development and a better understanding of the associated molecular events is important. The abnormal chromosome 20 in del(20q) AML has been shown to have lost a “Common Deleted Region” (CDR) that contains Protein Tyrosine Phosphatase Receptor T (PTPRT), a tyrosine phosphatase that is mutated in many human cancers such as AML. We have previously reported (MacKinnon et al, Genes, Chromosomes and Cancer 2010) that del(20q) also harbours an amplified “Common Retained Region,” (CRR) which contains Haemopoietic Cell Kinase (HCK). HCK is anoncogenic Src tyrosine kinase and its aberrant activation has been shown to contribute to the pathogenesis of some haematological malignancies.
We hypothesize that the amplification of HCK in the CRR cooperates with the loss of PTPRT in the CDR to cause AML. Our model proposes that AML occurs either through direct interaction between HCK and PTPRT, or through aberrant activation of Signal Transducer and Activator of Transcription 3 (STAT3), a cytoplasmic second messenger that is important in cellular signalling. Constitutively activated STAT3 has been shown to be oncogenic in several malignancies, including AML. STAT3 is a direct target of both HCK and PTPRT. It is phosphorylated (hence activated) by HCK, and dephosphorylated (hence inactivated) by PTPRT. This provides a downstream leukaemogenic pathway for our model. The ultimate aim of our experiments is to prove this hypothesis using mouse models. Murine haemopoietic stem cells (HSC) were isolated from the bone marrows of wild type C57BL/6 (WT) and PTPRT-null mice by Fluorescence Activated Cell Sorting for Lineage negative, C-kit and Sca-1 positive (LKS+) cells. Retroviral constructs of HCK were generated by cloning it into the retroviral vector pMSCViresEGFP(MIG), with GFP as reporter. Murine HSC were transduced with either retroviral HCK or MIG vector control and Phoenix cell system was used for retroviral packaging. Experiments using isolated LKS+ HSC were performed to examine for features of AML.
Examination of bone marrow cells from del(20q) AML patients by quantitative PCR revealed an increase in HCK mRNA expression and a reduction in PTPRT expression. Wild type (WT) and PTPRT-null murine HSC transduced with either MIG or HCK were cultured in methylcellulose media. Colony forming units (CFU) were enum |
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| ISSN: | 0006-4971 1528-0020 |