Mutation find may help leukaemia patients

Dr Cedric Tremblay (right) with a co-author,
PhD student Dr Sung Kai Chui.  The
research group has identified a cancer
promoting mutation. See paper.

by Anne Crawford

Researchers from Monash University’s Australian Centre for Blood Diseases (ACBD) have become the first scientists to describe the mechanisms by which a recently identified mutation makes leukaemia cells more aggressive. Their work is progressing in preclinical trials that may lead to the development of a drug to help treat patients with T-cell acute lymphoblastic leukaemia (T-ALL) who are resistant to conventional chemotherapy.

Gene mutations in T-cell acute lymphoblastic leukemia (T-ALL)

Image: American Society of Hematology

T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of T-cell progenitors, with overall survival rates of 70% in children and <40% in adults. The majority of T-ALL cases harbour activating mutations in NOTCH1, which encodes a membrane-spanning receptor essential for lineage commitment and development of T-lymphocytes. Activating NOTCH1 mutations occur in ~60% of human T-cell acute lymphoblastic leukemias (T-ALLs), and mutations disrupting the transcription factor IKZF1 (IKAROS) occur in ~5% of cases. These results demonstrate for the first time that aberrant NOTCH activity compromises IKAROS function in mouse and human T-ALL, and provide a potential explanation for the relative infrequency of IKAROS gene mutations in human T-ALL.

Reference: Witkowski MT, Cimmino L, Hu Y, Trimarchi T, Tagoh H, McKenzie MD, Best SA, Tuohey L, Willson TA, Nutt SL, Busslinger M, Aifantis I, Smyth GK, Dickins RA. Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia. Leukemia. 2015 Jun;29(6):1301-11. doi: 10.1038/leu.2015.27. Epub 2015 Feb 6.