., joined the Greehey Children's Cancer Research Institute in December of 2008 with major faculty responsibilities as a Principal Investigator in Hematologic Malignancies and as Assistant Professor in the Department of Medicine. Dr. Scott attended the University of Otago in Dunedin, New Zealand, where she received both her undergraduate and doctoral degrees in Biochemistry. Her research projects during this period were performed in the Molecular Carcinogenesis Laboratory under the tutelage of Dr. Tony Reeve. This was followed by postdoctoral fellowships in Pediatric Hematology (at the Johns Hopkins School of Medicine), and in Molecular Medicine (at the Fred Hutchinson Cancer Research Center). Dr. Scott was a faculty member in the Department of Medicine-Division of Hematology at the University of Washington (1998-2003), and, more recently, at the Department of Haematology at Cambridge University (2003-2008).

The goal of the Scott lab is to advance our understanding of normal and abnormal hematopoietic stem cell (HSC) biology, so that improved therapies can be developed for patients with hematologic malignancies. Our primary research interests have focused on the BCR/ABL-negative myeloproliferative neoplasms (MPNs), myeloid disorders that result from mutations acquired within the HSC compartment. Recently, several oncogenic disease alleles underlying the development of an MPN have been identified. We [Baxter, Scott, Campbell et al., Lancet 2005], along with groups in France, Switzerland and the US, reported the presence of a single “V617F” mutation in the JAK2 tyrosine kinase in a high proportion of patients with essential thrombocythemia (ET), polycythemia vera (PV), or primary myelofibrosis (PMF). As the result of genotype-phenotype studies performed on almost 800 DNA samples from the Medical Research Council PT1 study, we proposed that V617F-positive ET represents a forme fruste of PV [Campbell, Scott et al., Lancet 2005], with the disease phenotype depending on a combination of cell-intrinsic and -extrinsic factors. The subsequent observation that all PV patients carry a subclone of mutation-homozygous cells, whereas ET patients have only heterozygous JAK2 mutations [Scott et al., Blood 2006], suggests that most phenotypic differences between V617F-positive ET and PV depend primarily on the mutant gene dosage.

The molecular pathogenesis of the majority of those ET and PMF cases that lack the V617F mutation remains unclear. We have not detected alternate JAK or STAT mutations in these cases [Scott et al., Blood 2005]. However, distinct JAK2 mutations that occur in V617F-negative PV cases were identified [Scott et al., N. Engl. J. Med. 2007]. The “exon 12” JAK2 mutations result in a phenotype that is distinct from that of classic (V617F-positive) PV, characterized by a pronounced erythrocytosis, with little or no evidence of leukocytosis or thrombocytosis at diagnosis, and as a consequence may be present in patients diagnosed with idiopathic erythrocytosis (IE) [Percy, Scott et al., Haematologica 2007]. These mutations have not been detected in ET patients, but can occur in patients with post-polycythemic myelofibrosis [Scott et al., N. Engl. J. Med. 2007].

Currently, there is only a limited understanding of the downstream signaling consequences of these mutations; many important questions remain unanswered. In particular, it is unclear how V617F-heterozygous mutations result in a disorder primarily characterized by thrombocytosis, whereas V617F-homozygous mutations result in an erythrocytosis that is accompanied by leukocytosis and/or thrombocytosis, and the exon 12 mutations in an isolated erythrocytosis. Even more intriguing, perhaps, is the recent identification and characterization of unique JAK2 mutations associated with a lymphoproliferative, rather than a myeloproliferative, phenotype [Bercovich, Ganmore et al., Lancet 2008], a study we performed in collaboration with Dr Shai Izraeli and colleagues. These mutations, which almost always affect residue R683, are present in the leukemic blasts of 20% of the children with Down Syndrome that subsequently develop acute lymphoblastic leukemia (DS-ALL). The V617F, exon 12 and R683 JAK2 mutations all confer factor-independent cell proliferation in vitro, with similar activation of the JAK/STAT, MAPK and PI3K signaling pathways. It is hoped that studies that characterize the in vivo signaling consequences of each of these JAK2 mutations will lead to the eventual development of therapeutic agents capable of targeting select cell types whilst having no impact on others, and also shed insight into the lineage fate decisions normally mediated by JAK2 signaling.

The Scott group is also interested in the process of disease evolution in the MPNs, whether this is the transformation from a chronic to accelerated phase (ET or PV to myelofibrosis), or to a leukemic phase. It is anticipated that progression of these disorders will be driven by the acquisition of new, as yet unidentified, mutations, just as transformation from ET to PV results from mitotic (homologous) recombination to produce a V617F-homozygous cell [Scott et al., Blood, 2006]. Indeed, we have been studying additional mutations that confer a proliferative advantage to JAK2V617F-positive or MPLW515X cells in vitro and in vivo (Scott et al., in preparation), although these are not involved in disease transformation. Mutations such as these are likely to be both a consequence of the mutagenic properties of wildtype and mutant JAK2 overexpression, as reported by William Vainchenker’s group, and by the inhibition of apoptosis induced by DNA damage mediated by mutated JAK2 [Zhao et al., N. Engl. J. Med., 2008]. It is hoped that studies that identify the mutations that result in myelofibrotic transformation will assist the development of effective therapies for this disorder, and might also provide insight into the molecular events that drive disease progression in a variety of hematologic and solid tumors.