American Society of Hematology

Genomic Profiling and Chemical Biology: Opportunities for Novel Targeted Therapies in Hematologic Disorders

Genomic profiling of DNA and RNA has provided valuable new insights into the genetic basis of non-malignant and malignant hematologic disorders. These advances have important implications for future research and clinical practice, in such areas as molecular diagnostics, the implementation of precision medicine to guide which genes or pathway-directed therapies target disease within individuals, and the use of such information to inform drug discovery.

In all hematologic malignancies, including acute and chronic leukemias, lymphomas, and the myelodysplastic and myeloproliferative disorders, there are both inherited and somatic genetic alterations that contribute to predisposition, transformation, disease progression, responsiveness to therapy, and treatment complications. In addition, many non-malignant hematologic disorders have a genetic basis, including bone marrow failure syndromes, such as dyskeratosis congenita and severe congenital neutropenia, and hemoglobinopathies like sickle cell disease. In fact, extremely common genetic disorders that affect coagulation (e.g., Factor V Leiden) are an important cause of deep-vein thrombosis and pulmonary embolism.1 Historically, these genetic alterations have been identified by low-resolution genetic tests, like karyotyping or single gene assays. However, recent technological advances have enabled the analysis of genomic and epigenomic variation in a comprehensive, high-throughput fashion known as next-generation sequencing (NGS). Moreover, there is growing interest in a new area of research on the epi-transcriptome and its relevance to health and disease.

Utilization of these approaches has transformed the understanding of hematologic malignancies in recent years, with important implications for clinical care. Sequencing has helped explain that each tumor type typically exhibits distinct constellations of genetic alterations that target one or more key cellular pathways that regulate cell growth and proliferation, evasion of the immune system, and other aspects of cancer behavior. Sequencing can help identify different types of genetic alterations, including single nucleotide mutations, gains and losses of DNA, chromosomal rearrangements, and epigenetic modifications, that may be present in a tumor. In contrast, strategies that detect only a single type of genetic change (such as chromosome karyotyping) fail to identify all relevant genetic changes.

Integrated sequencing analysis has enabled the revision of the molecular classification of blood tumors and has uncovered genetic changes that may be used for classification and risk assignment. Further, new important targets have been identified with this technique, such as genetic and epigenetic changes that may be used as prognostic markers and for monitoring disease response; germline/inherited mutations for use in genetic counseling and disease surveillance; and pathways and genes that, when mutated, may serve as targets for new therapy.

Maximizing the Impact of Genomic Profiling: Priorities to Accelerate Progress
As genomic profiling is driving significant research progress across the field, it is essential to adopt this technology in drug discovery efforts and build the infrastructure to integrate genomic medicine into the clinic.

While important information has been generated from sequencing studies in various hematologic malignancies, for many subtypes of disease, an insufficient number of cases sequenced or a limited scope of sequencing has prevented researchers from gaining truly useful insights. This is particularly true for studies that have employed sequencing for only a limited portion of the tumor genome. Whole-genome sequencing of large numbers of samples, with an emphasis on poorly studied and rare entities, is required to fully define the landscape of genetic changes underlying the development of each disease. Further, the extent to which malignant cells are distinct from normal cells needs to be more broadly elucidated because many hematopoietic cancers disturb epigenetic regulators, including both readers and writers of the epigenome, of which there are many, providing additional precision medicine opportunities.

Such studies are likely to reveal important associations with outcome and targetable mutations. Support for ongoing sequencing is particularly important because high-resolution sequencing, beyond the completion of the initial phase of the National Institutes of Health (NIH)-led Cancer Genome Atlas, continues to uncover new genetic events that are critical for malignant transformation. An additional important area of investigation is the identification of the genetic alterations and genomic variations that are associated with therapy-related toxicity, long-term complications such as life-threatening cardiac toxicity, and the risk of secondary malignancies.

A better understanding of genetic and epigenetic alterations that drive hematologic diseases is essential to guide drug discovery efforts. Several recently approved drugs have achieved “breakthrough status” because of their remarkable promise for treating hematologic disorders that are tailored to specific genetic changes in tumor cells. Further, advanced genome sequencing studies have identified additional genetic changes that are attractive for similar targeted approaches. Opportunities and challenges will include:

1.1Defining the functional consequences of mutations to aid drug design;
1.2Generating new cell lines and animal models that recapitulate the many genomic alterations found in human tumors and that are amenable to high throughput sequencing efforts and making these tools available to the community;
1.3Developing pharmacokinetic, pharmacodynamic, and toxicology data for new drugs, including in tumor-bearing models, in efficient formats and timelines;
1.4Providing a rapid pathway for translation from preclinical studies to early-phase clinical trials;
1.5Developing a more advanced understanding of the functional consequences of mutations in disease subclones and the therapeutic targeting of complex cancer cell populations with evolving resistance mechanisms; and
1.6Developing an advanced understanding of modifications that occur at the epi-transcriptome level in normal and malignant hematopoietic processes as potential treatment opportunities.

While genome sequencing is becoming increasingly routine, accurate bioinformatic analysis remains challenging without "gold standard" approaches, particularly for complex sequence mutations and rearrangements. In addition, the sequencing and analysis process produces immense amounts of raw data that must be properly categorized. Accurate and consistent analysis is particularly important for clinical sequencing. An additional challenge is the variation in interrogating the non-coding genome (the 98 percent of the genome that is not transcribed into mRNA) and correlating the information with transcriptional and epigenetic data to provide a comprehensive, integrated portrait of cancer genomes. The immense amount of sequencing data often exceeds the capacity to perform adequate bioinformatic analyses, where both costs and the lack of trained personnel represent important limitations.

In order to integrate sequencing and analysis into both research and clinical applications, content-rich portals must be designed that can offer cost-effective and regulated access to raw genomic data for interrogating and sharing sequencing results without compromising patient privacy. To accomplish this, the following important areas must be addressed:

2.1Platforms must be sufficiently comprehensive to identify all relevant variant information;
2.2Bioinformatic analysis must be robust, with rapid return of results;
2.3Interpretation of the biologic and clinical relevance of genetic alterations must be reliable;
2.4The tools must be able to evaluate and report inherited genetic variants, including those that may have important impact outside of the clinical area of study; and
2.5The platforms must be housed in diagnostic environments that adhere to College of American Pathologist/Clinical Laboratory Improvement Act (CAP/CLIA) and Food and Drug Administration (FDA) regulations for appropriate applications.

An important prerequisite to proper clinical application of sequencing technology is establishing the clinical trial infrastructure to direct patients with “actionable” genetic or epigenetic alterations to trials of mutation-, gene-, or pathway-targeted agents. The need to organize this process efficiently is underscored by the fact that clinical sequencing will have to identify rare but traceable events (for example, anaplastic lymphoma kinase (ALK) or reactive oxygen species (ROS) mutations in non-small cell lung cancer may serve as an appropriate analog).

Therefore, the organization and implementation of clinical sequencing will require structural changes in the health-care sector:

3.1Creation of genome diagnostic networks to address accrual of sufficient patients to enable adequate power; procurement of suitable tumor/non-tumor material for sequencing, pharmacodynamic studies, and correlative biology; and engagement of the pharmaceutical industry to support trials of new or repurposed agents, particularly in uncommon diseases or special populations (such as the elderly, young children, or those with other medical conditions).
3.2Adoption of novel adaptive clinical trial designs that will help consolidate research timelines and offer better utility for studying specific biomarkers or patient subpopulations.
3.3Development of a new regulatory model for rapid testing of novel agents in single patients with specific genetic alterations that may transect traditional boundaries in drug development when novel combinations from different sources may be indicated.


  1. Reitsma, PH. Genetics in thrombophilia. An update. Haemostaseologie. 2014 Dec 3;35(1).
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