View all of John Dick’s publications in Pubmed.
Most Significant Contributions
1. The development of xenograft assays. Dr. Dick developed the first system, modeled after clinical transplantation, for transplanting human hematopoietic cells into immune-deficient mice with resultant multilineage repopulation of murine hematopoietic tissues (Science 88; 92). In parallel, he developed the first xenograft models of human leukemia (B-ALL, AML, CML) that reflected growth of the human disease (Science 89, Nature 94). This xenograft assay has attained worldwide acceptance as the “gold standard” for detecting human HSC and LSC and has been adopted for evaluating many therapeutics. His pioneering work has stimulated the development of xenograft assays for other human solid tumors and diseases and, more broadly, has played a role in steering the research community towards studying primary human normal and malignant tissues. In his research to improve xenograft efficiency, he found that macrophages govern human HSC engraftment through Sirp-α (Nature Imm 07), opening a therapeutic avenue to aid HSC transplantation and target human LSC (J Exp Med 12)
2. The elucidation of the roadmap of human hematopoiesis and isolation of human HSC. During the last three decades, Dr. Dick has provided insight into the composition and heterogeneity of the human HSC pool. Using retroviral clonal tracking, a method he pioneered as a post-doctoral fellow (Cell 85), he made a series of seminal findings including: identification of different classes of human HSC with short- and long-term- repopulating capacity (Nature Imm 01); proof of heterogeneity in repopulation derived from variable self- renewal capacity suggesting that HSC fate might be unpredictable and governed by stochastic elements prior to entering more rigid downstream developmental programs (Nature Imm 06); insight into how human hematopoietic homeostasis is maintained through persistence of self-renewing HSC following an initial period of clonal instability, a result inconsistent with the clonal succession model. He has made a series of improvements to improve the sensitivity of the repopulation assay that resulted in identifying HSC classes, including one that rapidly generates high levels of human myeloid and erythroid cells (Nat Med 03), a finding with important utility for clinical therapeutics that require rapid repopulation. This work has grown into a novel sorting approach that was combined with single cell functional assays and culminated in the first isolation of near-pure populations of ten human HSC and progenitor fractions (Nat Imm 10, Science 11). Transcriptional profiling of these populations has yielded the first comprehensive analysis of the molecular regulation of early fate determination in human hematopoiesis (Nat Imm 13; Cell Stem Cell 14) and the recognition that proteostatic stress signaling is differentially wired in HSC (Nature 16). The discovery of a unique multi-lymphoid progenitor that retains myeloid potential provides the first evidence that a rigid myeloid-lymphoid segregation does not occur in humans (Nat Imm 10, 13). Similarly, remapping of myeloid, erythroid and megakaryocytic origins has changed the textbook view of the human blood hierarchy (Science 16). Finally, the isolation of human HSC in its purest form,⎯as a single HSC capable of regenerating the entire blood system represents an achievement that will advance our understanding of human HSC biology, as well as enable substantial improvement in the clinical application of HSC-based therapies (Science 11).
3. The discovery of stemness properties in human leukemia and colon cancer. Dr. Dick uncovered the first prospective purification of LSC, distinct from clonogenic AML progenitors and blasts, establishing that the neoplastic clone is hierarchically organized and sustained by self-renewing LSC. This finding resolved a long- standing question in cancer biology, providing the first conclusive validation of the CSC hypothesis (Nature 94). This work is credited with stimulating the subsequent discovery of CSC in solid tumors and ongoing research to determine which tumours adhere to this model. He was the first to identify the human colon cancer-initiating cell, establishing that human colon cancer is also hierarchically organized (Nature 07). He has provided a deep understanding of LSC and colon CSC. His findings that LSC from different AML subtypes have similar cell surface properties, quiescence, repopulation and self-renewal potential (Nat Med 97; Nature Imm 05), and transcriptional programs (Nat Med 11) to normal HSC, indicating shared determinants of stemness. His discovery that stemness programs identified based on functionally defined LSC (and HSC) are highly predictive of patient survival established that LSC and stemness programs are clinically relevant (Nature Med 11, Nature 16). He found that CD44 is essential for LSC trafficking to supportive niches and that treatment with anti-CD44 eradicated primary AML growth in xenografts (Nat Med 06). This result, together with work on targeting LSC with anti-CD123 (Cell Stem Cell 09), represents the first LSC-targeted therapies that have moved to clinical trial. He also developed the first humanized experimental leukemogenesis models by transducing primary human hematopoietic cells with oncogenes and generating leukaemia in xenografts identical to the human disease (Science 07), ushering in a new era of cancer models utilizing primary human hematopoietic cells.
4. The unification of CSC and genetic diversity models of tumor heterogeneity. The CSC and genetic evolution models describing tumor cell heterogeneity have often been viewed as mutually exclusive. By combining functional leukemia-initiating cell assays with genetic analysis, Dr. Dick challenged this view and showed that leukemia-initiating cells (L-IC) within B-ALL are genetically diverse and evolve through complex evolutionary lineage relationships (Nature 2011). This sets the stage for a unified view of cancer that accommodates both heterogeneity models. More generally, the isolation of individual genetic subclones in xenografts provides essential proof for the existence of functional subclones that have been predicted from gene sequencing, providing a framework to use xenograft isolation as a means to develop therapies that ensure that all subclones are targeted thereby reducing the risk of recurrence. In a second series of paradigm-shifting studies, Dr. Dick found that colon cancer cells display inherent functional variability in tumor propagation potential, including one class that was dormant, yet the mutated cancer genes were identical for all of these different cell behaviours. Importantly, the effect of chemotherapy was also variable with dormant cells being highly tolerant. This research challenges the conventional wisdom that the variable growth properties and resistance to therapy of cancer cells are solely based on the genetic mutations within a tumour. Instead, this work firmly establishes that, in addition to genetic mutations, non-genetic determinants govern cancer cell growth and therapy tolerance (Science 13). Further evidence linking stemness and evolution has come from his recent studies establishing the existence of ancestral stem and progenitor cells in the diagnostic and remission samples of AML patients that only contain single early mutations (e.g. DNMT3a mutation) thereby defining clonally expanded pre-leukemic HSC (preL-HSC) (Nature 2014) and from paired analysis of diagnosis and relapse AML samples where the cell of origin of relapse was linked to stem cells (Nature 2017). Through large cohort studies, these studies have shown that preL-HSC can be found in the general population and define individuals at risk for progression to AML up to a decade in advance and thereby providing a rationale for prevention strategies in AML (Nature 2018). Thus these studied have elucidated the full arc of leukemia development from the cell of origin, the initiating mutation, and the consequences of this mutation in the targeted cell, the creation of genetically diverse leukemia stem cells and finally the origin of relapse initiating cells. These findings provide an opportunity for improved clinical monitoring of AML patients.