Petter Woll group
Impact of alternative splicing on normal and malignant hematopoietic stem cell biology
Because of their short half-life, millions of mature blood cells of multiple lineages are continuously replenished from a rare population of uncommitted hematopoietic stem cells (HSCs) which possess the unique ability to self-renew and to develop towards all blood cell lineages.
Understanding the precise mechanisms involved in the regulation of this process is of considerable relevance for human health and disease, as these regulatory stages frequently are hijacked in hematologic malignancies. While alternative splicing is thought to represent an important level of regulation of normal development, its role in normal hematopoiesis remains unknown.
However, recently highly recurrent and mutually exclusive mutations in key components of the mRNA splicing machinery has been identified in hematologic malignancies, in particular in patients with myelodysplastic syndromes, highlight the impact of dysregulated splicing in malignant transformation within the hematopoietic hierarchy.
The major focus of our research program is towards the development and characterisation of clinically relevant genetic mouse models for recurrent splicing mutations in part to understand the cellular and molecular targets for these mutations. In parallel we will pursue loss- and gain-of-function studies to understand the role of these regulators in normal hematopoiesis. Mouse models will also be complement with studies of hematopoiesis in patients with the same splicing mutations.
Petter S. Woll, Group Leader, Assistant Professor
Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo.
Cancer Cell 2014 Jun;25(6):794-808
Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy.
Nature 2013 Oct;502(7470):232-6
Lymphomyeloid contribution of an immune-restricted progenitor emerging prior to definitive hematopoietic stem cells.
Cell Stem Cell 2013 Nov;13(5):535-48
Quiescent leukaemic cells account for minimal residual disease in childhood lymphoblastic leukaemia.
Leukemia 2013 Apr;27(5):1204-1207
FLT3-ITDs instruct a myeloid differentiation and transformation bias in lymphomyeloid multipotent progenitors.
Cell Rep 2013 Jun;3(6):1766-76
The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential.
Nat. Immunol. 2012 Feb;13(4):412-9
Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia.
Cancer Cell 2011 Jan;19(1):138-52
Persistent malignant stem cells in del(5q) myelodysplasia in remission.
N. Engl. J. Med. 2010 Sep;363(11):1025-37