Lethal giant larvae 1 tumour suppressor activity is not conserved in models of mammalian T and B cell leukaemia

Edwin D Hawkins; Jane Oliaro; Kelly M Ramsbottom; Stephen B Ting; Faruk Sacirbegovic; Michael Harvey; Tanja Kinwell; Jacques Ghysdael; Ricky W Johnstone; Patrick O Humbert; Sarah M Russell

doi:10.1371/journal.pone.0087376

Lethal giant larvae 1 tumour suppressor activity is not conserved in models of mammalian T and B cell leukaemia

PLoS One. 2014 Jan 27;9(1):e87376. doi: 10.1371/journal.pone.0087376. eCollection 2014.

Affiliations

¹ Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia ; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
² Stem Cell Research Group, Australian Centre for Blood Diseases, Monash University and Alfred Health, Melbourne, Victoria, Australia.
³ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia ; Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁴ Institut Curie, Centre Universitaire, Bat 110 91405, Orsay, France ; Centre National de la Recherche Scientifique UMR 3306, Orsay, France ; INSERM (Institut National de la Santé et de la Recherche Médicale) U1005, Orsay, France.
⁵ Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia ; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia ; Centre for Micro-Photonics, Swinburne University of Technology, Hawthorn, Victoria, Australia.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Marrow Transplantation
Cell Lineage / physiology
Cytoskeletal Proteins
DNA Primers / genetics
Disease Models, Animal*
Hematopoietic Stem Cells / metabolism
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Kaplan-Meier Estimate
Leukemia, B-Cell / metabolism*
Leukemia, T-Cell / metabolism*
Mice
Mice, Knockout
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*

Substances

Cytoskeletal Proteins
DNA Primers
Homeodomain Proteins
Llgl1 protein, mouse
Tumor Suppressor Proteins

Grants and funding

The work was funded by the Australian National Health and Medical Research Council (NHRMC, project grants and fellowships to EDH, JO, SMR, POH, RWJ, SBT), the Human Frontiers Science Program, the Australian Research Council (ARC, fellowship to SMR) and the Australian Cancer Research Foundation (ACRF, ACRF Cell Biology Program). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.