Finding boosts target hopes for aggressive blood cancers

2016 Mammalian Functional Genetics Laboratory group
L- R: Dr Katharina Haigh, Mr John Drummond, Mr Mina Takawy,
Dr Catherine Carmichael, Assoc Prof Jody Haigh, Dr Maggie Costa,
Absent: Dr Thao Nguyen

by Anne Crawford 

In September last year this blog reported on some promising findings into ZEB2, a protein implicated in certain aggressive leukaemias, made by Australian Centre for Blood Diseases (ACBD) researcher, Associate Professor Jody Haigh as part of an international collaboration.

Associate Professor Haigh’s work has since been bolstered by the revelation of a novel partner of ZEB2. Combined, they may form a possible therapeutic target that could potentially have greater efficacy than targeting ZEB2 alone.

Publication: Novel biological insights in T-cell acute lymphoblastic leukemia

Figure 2. Molecular mechanisms for IL7R/JAK/STAT
activation in T-cell acute lymphoblastic leukemia (T-ALL).

Review article on T-cell acute lymphoblastic leukemia (T-ALL), an aggressive type of blood cancer that accounts for about 15% of pediatric and 25% of adult acute lymphoblastic leukemia (ALL) cases. It is considered as a paradigm for the multistep nature of cancer initiation and progression. T-ALL originates from T-cell precursors at different stages of their development and is characterized by distinct and well characterized molecular genetic subtypes. Children affected by this disease respond fairly well to high-dose chemotherapy regimens. Unfortunately, the clinical response in adults remains problematic, and therapeutic options for relapsed T-ALL patients remain scarce.

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.