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The Making of a Model

By James Dugan, MD, and Bradley Haverkos, MD, MPH

Despite what the title of this article may suggest, plenary 5 was not focused on a new hit show on the ABC network. Our definitions of acute myeloid leukemia (AML) have changed as our understanding of the disease has evolved. An emphasis on morphology in the French-American-British criteria took a back seat to the prognostic value of genetic abnormalities in the World Health Organization (WHO) criteria. The European Leukemia Network criteria now includes molecular phenotypes that have become even more important as we develop more mutation-specific therapies.

Ilaria Iacobucci, PhD

No matter how subdivided our criteria become, the information from all three systems, and the systems to come, will need to be merged with new discoveries that can be used to guide treatment. Acute erythroleukemia (AEL), or AML-M6, is a rare, poorly understood variant of AML. According to WHO, AEL is defined as having at least 50 percent erythroid precursors and myeloblasts that account for no less than 20 percent of the nonerythroid cell population. Previous research has proven AEL to be a cytogenetically heterogenous disease; one with a poor response to standard chemotherapy and poor prognosis. Under the primary authorship of Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital, the story told during the presentation of abstract #5 worked to improve our understanding of the molecular aberrations that define AEL, which may be used to guide future clinical trials in this high-risk phenotype.

Genomic analysis identified five age-related AEL subtypes based on distinct mutation profiles. The authors then employed CRISPR/Cas9 genome editing to induce combinations of loss-of-function mutations in nine of the identified genes. The authors were able to show that by editing specific combinations of genes seen in patients with AEL, they were able to promote the development of AEL in their animal model. Confirmation of the development of this high-fidelity model of erythroleukemia allowed the authors to explore drug sensitivity. Charles Mullighan, MD, MBBS (Hons), of St. Jude Children’s Research Hospital summarized their work: “For this study, we addressed whether co-modeling of the co-occurring genomic alterations seen in different types of erythroleukemia can recapitulate the disease. Using CRISPR/Cas9 genome editing of mouse hematopoietic progenitors, this was shown to be the case, with distinct groups of genetic alterations driving the development of leukemia mirroring that seen in patients. Moreover, these models were used in drug screening approaches, and genotype-specific drug vulnerabilities were identified. The results validate the role of these mutations in leukemogenesis and provide the framework for genotype-specific tailored therapeutic approaches in patients.”

The authors conclude that they were able to successfully generate genetically defined models of AEL and show that sensitivity to different classes of compounds is dependent on specific molecular phenotypes. The morphologic subtype of AML known as acute erythroleukemia confers a poor prognosis. Using the information presented, we may be able to systemically choose treatment regimens based on known molecular aberrations that offer improved survival compared with traditional chemotherapy. The authors’ method of modeling the disease may prove useful for testing unique compounds and drug regimens in other subtypes of AML.

Drs. Dugan and Haverkos indicated no relevant conflicts of interest.

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