AML results from a series of genetic changes in haematopoietic precursor cells. Altered haematopoietic growth and differentiation results in accumulation of large numbers of abnormal white blood cells in the bone marrow. These cells are capable of dividing and proliferating, but cannot differentiate into mature haematopoietic cells. Genetic changes in AML include mutations in oncogenes and the loss of tumour-suppressor genes. The EU-funded project 'In vitro and in vivo screens for novel regulators in leukemia' (NOREL) focused on identifying new factors involved in AML. Researchers focused on genes whose products can be inhibited by small molecules. Such genes can be targeted in the future by novel cancer-specific therapies. Short hairpin RNA (shRNA) screening with high-throughput sequencing was used in the project. A general toxicity control of shRNAs included normal mouse bone marrow cells. Several genes were identified in a screening approach. Depletion of these genes inhibited the growth of leukaemic cells but had no or little effect on normal cells. A pooled shRNA library, targeting all major families of chromatin writers, erasers and readers (a total of 319 genes), was used. In vivo screening was performed in MLL-AF9 mice. One of the genes selected by screening was Jmjd1c. This gene is required for leukaemia maintenance in vitro and in vivo. Human and mouse leukaemic cells with depleted levels of Jmjd1c undergo apoptosis. Down-regulation of Jmjd1c affects gene expression of Myb and Myc and leukaemic stem cell signature. While previously believed to be an H3K9me2/me1 demethylase, Jmjd1c lacked the activity towards H3K9 methyl marks. The NOREL project identified several potential therapeutic targets in leukaemia and validated them in pre-clinical models. Complete characterisation of these targets will be the subject of a future study.
Acute myeloid leukaemia, leukaemia, oncogenes, tumour suppressors, short hairpin RNA