I was born and raised in Dunedin, New Zealand, where I also obtained a first-class B.Sc.(Hons.) degree from the University of Otago in 1986 and a Ph.D. in 1991. Whilst these degrees were conferred by the Department of Biochemistry, my undergraduate and postgraduate studies employed molecular biology techniques to focus on the genetic basis of human malignancies, particularly chronic myeloid leukemia (CML) and nephroblastoma. These studies were performed in the laboratory of Dr. Tony Reeve, one of New Zealand’s foremost cancer geneticists.

After graduation, I pursued a postdoctoral fellowship at the Johns Hopkins Medical Institutes (1991-1993) with Dr. Alan Friedman, where I reported for the first time the hematopoietic expression pattern of members of the C/EBP family of transcriptional activators, and evaluated the role of C/EBP in the transcriptional regulation of myeloid differentiation. I then undertook a second fellowship with Dr. Steve Collins at the Fred Hutchinson Cancer Research Center (1994-1995), where I identified and characterized several novel downstream targets of the truncated retinoic acid receptor in an in vitro model of acute promyelocytic leukemia (APL). It was during the latter of these fellowships that I became particularly interested in the molecular and cellular biology of hematopoietic stem cells (HSCs).

For the last decade, my primary research interest has been the MPNs, which are myeloid malignancies that result from mutations acquired within the HSC compartment. In this period, several oncogenic disease alleles that underlie the development of an MPN were identified. We, along with colleagues in France, Switzerland and the US, identified and functionally characterized a single amino acid mutation, “JAK2V617F”, in the JAK2 tyrosine kinase [Baxter, Scott, Campbell et al., Lancet 2005]. This mutation is present in the majority of patients with essential thrombocythemia (ET), polycythemia vera (PV), or primary myelofibrosis (MF), and appears to be the driving mutation in these disorders, since a JAK2V617F knock-in mouse model invariably develops an MPN-like disorder [Li et al., Blood 2010].

For several years after this discovery, the causative mutation in MPN patients that lack the JAK2V617F mutation remained unclear; in a targeted sequencing approach, we did not detect alternate JAK or STAT mutations in individuals with JAK2V617F-negative ET or MF [Scott et al., Blood 2005]. However, distinct JAK2 mutations that occur in JAK2V617F-negative PV cases were subsequently identified [Scott et al., NEJM 2007]. These “exon 12” JAK2 mutations result in a phenotype that is distinct from that of classic (JAK2V617F-positive) PV, and which is characterized by a pronounced erythrocytosis, with minimal leukocytosis or thrombocytosis [Percy et al., Haematologica 2007; Scott, Am J Hematol 2011].

An appreciation for this phenotypic difference led the World Health Organization to modify their diagnostic criteria for PV to include a subset of patients that would not have received a correct diagnosis under existing criteria. Identification of the JAK2V617F and JAK2 exon 12 mutations has been of particular clinical importance, providing in part the impetus for the initiation of Phase I/II clinical trials of JAK inhibitors for the treatment of MPN patients. The completion of Phase III trials of one such compound has resulted in its approval by the Federal Drug Administration for the treatment of patients with MF.

Research interests

The long-term goal of the Scott laboratory is to advance our understanding of normal and abnormal hematopoietic stem cell (HSC) biology, so that improved therapies can be developed for patients with a variety of different hematologic malignancies.

Currently, our group is particularly interested in the process of disease evolution in the MPNs, whether this is the transformation from a chronic phase (ET or PV) to an accelerated phase (MF) or an acute myeloid leukemia (AML). It is thought that progression of these disorders is driven by the acquisition of secondary mutations, just as transformation from ET to PV is associated with mitotic recombination that produces a JAK2V617F-homozygous cell [Scott et al., Blood 2006]. These secondary mutations are likely to be both a consequence of the mutagenic properties of wildtype and mutant JAK2 expression, and by the inhibition of apoptosis induced by DNA damage mediated by mutated JAK2 [Zhou et al. NEJM 2008]. Amongst the secondary mutations identified thus far are several that confer a proliferative advantage to JAK2V617F-positive or MPLW515L-positive hematopoietic cells both in vitro and in vivo, but that are not involved in disease transformation [Scott et al., submitted]. Several others may be involved in myelofibrotic transformation. The identification of the mutation(s) that drive myelofibrotic transformation will assist in the development of more effective, targeted therapies for patients with this disorder, and may also provide insights into the molecular events that drive disease evolution in other hematologic and solid tumors.

An emerging theme in malignant hematopoiesis is the acquisition of mutations affecting proteins that regulate chromatin structure and consequent gene expression. For example, subgroups of patients with an MPN or a myelodysplastic syndrome (MDS) acquire loss-of-function mutations in TET2. Members of TET family catalyze the conversion of 5’methylcytosine to 5’-hydroxymethylcytosine, and so are pivotal to the transcriptional activation of genomic loci silenced by methylation. Mutations in TET2 do not cause myelofibrotic or leukemic transformation in patients with an MPN, and do not significantly affect prognosis. Instead, by a mechanism that remains unclear, they provide a competitive in vivo advantage to mutation-bearing HSCs. The identification of regions of the HSC genome epigenetically altered as a result of TET2 mutation will provide insights into the dysregulated gene expression that contributes to disease evolution in affected MPN or MDS patients, and should assist in the development of targeted therapies for both types of hematologic malignancy. In work funded by the Congressionally-Directed Medical Research Program (CDMRP) Bone Marrow Failure Syndromes Program, we have used an HSC model system and RNA interference (RNAi)-mediated knockdown to mimic these loss-of-function TET2 mutations.

We will explore the consequent effects on chromatin structure using next-generation sequencing-based strategies to develop genome-wide maps of chromatin compaction and thereby identify changes in chromatin accessibility within HSCs that directly result from reduced TET2 expression. This experimental approach will be adopted to mimic other disease-associated mutations that target chromatin modifiers (such as DNMT3A, ASXL1 and EZH2), which should provide further insights into the molecular heterogeneity of the MPNs.

In addition to MDS, the Scott group has an interest in the biology of pediatric acute lymphoblastic leukemia (ALL), arising from our involvement in the identification of a third type of activating JAK2 mutation. These JAK2 mutations are found in ~25% of patients with Down syndrome-associated ALL [Bercovich et al., Lancet 2008; Scott, Blood Reviews 2013], as well as in a smaller fraction of high-risk sporadic ALL cases, and provide the rationale for Phase I/II trials of JAK inhibitors in these patient groups.

Research projects

  • Molecular pathogenesis and clonal evolution of the myeloproliferative neoplasms
  • Role of dysregulated JAK/STAT signalling in hematologic malignancies
  • Epigenetic regulation in normal hematopoietic stem cells and their malignant equivalents
  • Molecular basis of leukemogenesis

Areas of research