View all of John Dick’s publications in Pubmed.
Most Significant Contributions
1. Developing Xenograft Assays. We developed the first system for transplanting human hematopoietic cells into immune-deficient mice with resultant multilineage repopulation of murine hematopoietic tissues. The xenograft assay has attained worldwide acceptance as the “gold standard” for detecting human hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). We also developed the first xenograft models of human lymphoid leukemia (B-ALL), acute myeloid leukemia (AML) and chronic myeloid leukemia. Our pioneering work stimulated the development of xenograft assays for other human solid tumours and diseases. (Science 88, 89, 92)
2. Elucidating the Roadmap of Human Hematopoiesis. By improving the xenograft assay and devising new cell sorting schemes, we enriched and characterized classes of human HSCs and progenitors and through multi-omics analyses we elucidated the molecular mechanisms underpinning their functional properties. We developed methods to isolate near-pure populations of human HSCs, a breakthrough that enabled the transcriptional profiling 13 HSC, progenitor and differentiated cell types. More recently, we carried out a comprehensive series of single-cell analyses, which produced findings that challenged the traditional hierarchy of blood development and led to elaboration of new models for human hematopoiesis. (Nat Immunol 01, 06, 10, 13; Nat Med 03; Science 11, 16; Cell Stem Cell 12, 14, 15; Nature 14; Cancer Cell 16)
3. Discovering Stemness Properties in Human Leukemia and Colon Cancer. We were the first to purify LSCs, thereby establishing that the neoplastic clone is hierarchically organized and sustained by self-renewing LSCs. We were also the first to identify the human colon cancer-initiating cell, establishing that human colon cancer is also hierarchically organized. Our subsequent work has provided a deep understanding of the biology of LSC and colon cancer-initiating cells. We provided the first formal proof that the determinants of stemness are clinically relevant in AML, which led to the development of a robust stemness-based prognostic/predictive test for AML. Moreover, our findings have enabled the development of new drugs that target LSCs, three of which entered clinical trials. (Nature 94, Nat Med 97, Nat Immunol 04, Nat Med 06, Science 07, Nature 07, Cell Stem Cell 09, Nat Med 11, Nature 16)
4. Unifying the CSC and Genetic Diversity Models of Tumour Heterogeneity. Our work has provided a foundation for unifying the CSC and genetic evolution models of tumour cell heterogeneity, which were previously viewed as mutually exclusive. We have shown that leukemia-initiating cells in B-ALL are genetically diverse and evolve through complex evolutionary lineage relationships. We have also found that colon cancer cells display variability in tumour propagation potential and chemotherapy response, yet the mutated cancer genes were identical for all of these different cell behaviours. This work firmly established that, in addition to genetic mutations, non-genetic determinants govern cancer cell growth and therapy tolerance. Further evidence reconciling CSC and evolution models has come from our recent studies establishing the existence of ancestral, pre-leukemic stem and progenitor cells in the diagnostic and remission samples of AML patients that contain only single early mutations (DNMT3a mutation) and not the full mutational burden of the AML blasts. (Nature 11; Science 13; Nature 14)