Abstract
In epithelial and stem cells, lethal giant larvae (Lgl) is a potent tumour suppressor, a regulator of Notch signalling, and a mediator of cell fate via asymmetric cell division. Recent evidence suggests that the function of Lgl is conserved in mammalian haematopoietic stem cells and implies a contribution to haematological malignancies. To date, direct measurement of the effect of Lgl expression on malignancies of the haematopoietic lineage has not been tested. In Lgl1−/− mice, we analysed the development of haematopoietic malignancies either alone, or in the presence of common oncogenic lesions. We show that in the absence of Lgl1, production of mature white blood cell lineages and long-term survival of mice are not affected. Additionally, loss of Lgl1 does not alter leukaemia driven by constitutive Notch, c-Myc or Jak2 signalling. These results suggest that the role of Lgl1 in the haematopoietic lineage might be restricted to specific co-operating mutations and a limited number of cellular contexts.
Highlights
In Drosophila, the Scribble complex protein, Lethal giant larvae (Lgl) is a potent tumour suppressor
The role of Lgl1 in the regulation of haematopoiesis described by Heidel et al might be restricted to haematopoietic stem cells (HSC) function and, not broadly applicable subsequent components of the haematopoietic system
We observed no development of leukaemia in primary chimeric mice consistent with previous studies using conditional Lgl1 deletion [15]
Summary
In Drosophila, the Scribble complex protein, Lethal giant larvae (Lgl) is a potent tumour suppressor. Lgl maintains epithelial cell polarity [1,2,3] and regulates asymmetric cell division (ACD), which produces unique daughter cells through the uneven distribution of cell fate determinant proteins during cell division. Homozygous Lgl mutant Drosophila develop epithelial tumours [4] and cooperate with Notch to drive epithelial neoplasia [5]. Mice deficient in Lgl die neonatally from neuro-ectodermal tumours correlating with mislocalisation of the Notch regulator Numb, and consequent impaired ACD in neuronal precursors [6]. Within the mammalian hematopoietic system, Notch signalling has been implicated in both the generation of haematopoietic stem cells (HSC), and in the regulation of their self-renewal [11,12]. The asymmetric localisation of Notch/Numb has been implicated in both normal HSC and leukemic daughter cell fate [13]. 50% of T-cell acute lymphoblastic leukaemia (T-ALL) patients possess mutations that constitutively activate Notch signalling [14] identifying regulators of this pathway as key components in leukaemia pathology
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