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Research Spotlight: Understanding the Heterogeneity of Myeloid Malignancies

  • Advances in Hematologic Malignancies Issue 4 Summer 2016
  • Advances in Hematologic Malignancies Issue 4, Summer 2016

    R. Coleman Lindsley, MD, PhD

    R. Coleman Lindsley, MD, PhDR. Coleman Lindsley, MD, PhD

    The myeloid malignancies, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN) are a spectrum of biologically related, but clinically heterogeneous diseases. In part, the differences between patients are driven by the particular combination of genetic mutations each disease acquires during its evolution. We combine systematic analysis of human disease samples with detailed studies in faithful laboratory models to identify mechanisms of disease progression and therapeutic response in myeloid malignancies.

    Ontogeny of AML: A major focus of our research is on understanding the genetic basis of clinical heterogeneity in the myeloid malignancies. By studying cohorts of highly selected AML cases, we defined a core set of mutations, termed secondary-type mutations, that is highly specific for AML that arises in transformation of prior myelodysplastic syndromes (secondary AML, sAML) (Lindsley, et al. Blood, 2015). Importantly, the presence of these mutations highlights a subgroup of AML patients without a prior diagnosis of MDS who have a genetically defined, sAML-like disease. This novel subtype of AML is particularly common among patients over 60 years old and is associated with adverse clinical outcomes compared to patients of a similar age without the sAML signature. This discovery enables the objective, prospective allocation of AML patients into clinically distinct ontogeny sub-groups, thus serving as a potential platform for risk stratification and focused investigation of novel therapeutics.

    MDS transplant genomics: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only therapeutic intervention for MDS patients with curative potential, but clinical decisions about the timing and approach of HSCT are complex and confounded by the marked heterogeneity within current MDS diagnostic and prognostic schema. We are leading a collaboration with the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National Marrow Donor Program (NMDP) biorepository to study the clinical impact of somatic genetic mutations in a cohort of 1528 MDS patients from 130 transplant centers. This comprehensive analysis has identified associations between pre-HSCT MDS genetic alterations and post-HSCT relapse and survival outcomes. Based on these results, we are developing a novel, transplant-specific MDS genetic prognostic scoring system that can be integrated into clinical decision-making regarding transplant timing and patient selection.

    The Rapid Heme Panel — leukemia genetics in "real time": A fundamental goal of our approach to clinical genomics is to enable a flexible and rapid interplay between genomic research findings and innovative clinical investigation. Therefore, in collaboration with the Center for Advanced Molecular Diagnostics and the Department of Pathology at Brigham and Women's Hospital, we co-led the development of a clinical sequencing platform for patients with hematologic malignancies (the "Rapid Heme Panel"). Rapid Heme Panel (RHP) uses targeted deep sequencing to test for mutations and copy number alterations in a panel of 95 genes involved in the pathogenesis of hematologic malignancies. In the clinical setting, RHP results are used for diagnosis, risk stratification, detection of disease progression or relapse, and clinical trial enrollment. Since RHP has been fully integrated into clinical practice at Dana-Farber/Brigham and Women's Cancer Center, the genetic profile and clonal dynamics of all myeloid leukemia patients are systematically and prospectively catalogued. This rich clinical dataset affords a unique opportunity to leverage clinical observations into discoveries about mechanisms of disease progression and therapy resistance.

    heterogeneity of myeloid malignancies diagram