Acute myeloid leukemia in the era of precision medicine: recent advances in diagnostic classification and risk stratification

The completion of the Human Genome Project in 2003 has led to significant advances in patient care in medicine, particularly in diagnosing and managing genetic diseases and cancer. In the realm of genetic diseases, approximately 15% of critically ill infants born in the U.S.A. are diagnosed with genetic disorders, which comprise a significant cause of mortality in neonatal and pediatric intensive care units. The introduction of rapid whole-genome sequencing (rWGS) as a first-tier test in critically ill children with suspected, undiagnosed genetic diseases is a breakthrough in the diagnosis and subsequent clinical management of such infants and older children in intensive care units. Rapid genome sequencing is currently being used clinically in the USA, the UK, the Netherlands, Sweden, and Australia, among other countries. This review is intended for students and clinical practitioners, including non-experts in genetics, for whom it provides a historical background and a chronological review of the relevant published literature for the progression of pediatric diagnostic genomic sequencing leading to the development of pediatric rWGS in critically ill infants and older children with suspected but undiagnosed genetic diseases. Factors that will help to develop rWGS as a clinical test in critically ill infants and the limitations are briefly discussed, including an evaluation of the clinical utility and accessibility of genetic testing, education for parents and providers, cost-effectiveness, ethical challenges, consent issues, secondary findings, data privacy concerns, false-positive and false-negative results, challenges in variant interpretation, costs and reimbursement, the limited availability of genetic counselors, and the development of evidence-based guidelines, which would all need to be addressed to facilitate the implementation of pediatric genomic sequencing in an effective widespread manner in the era of precision medicine.

Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single-guide RNA (sgRNA)-based gene editing since the first report of repetitive sequences of unknown significance in 1987 is fascinating, highly instructive, and inspiring for future advances in medicine. The recent approval of CRISPR-Cas9-based gene therapy to treat patients with severe sickle cell anemia and transfusion-dependent β-thalassemia has renewed hope for treating other hematologic diseases, including patients with a germline predisposition to hematologic malignancies, who would benefit greatly from the development of CRISPR-inspired gene therapies. The purpose of this paper is three-fold: first, a chronological description of the history of CRISPR-Cas9-sgRNA-based gene editing; second, a brief description of the current state of clinical research in hematologic diseases, including selected applications in treating hematologic diseases with CRISPR-based gene therapy, preceded by a brief description of the current tools being used in clinical genome editing; and third, a presentation of the current progress in gene therapies in inherited hematologic diseases and bone marrow failure syndromes, to hopefully stimulate efforts towards developing these therapies for patients with inherited bone marrow failure syndromes and other inherited conditions with a germline predisposition to hematologic malignancies.

To evaluate feasibility of assessing T-cell receptor γ (TRG) clonality by next-generation sequencing (NGS) in hematolymphoid tissues. We evaluated TRG clonality using NGS and polymerase chain reaction (PCR) assays in blood, bone marrow, and formalin-fixed, paraffin-embedded tissues in 41 archived cases, including 21 benign cases with no history of any lymphoproliferative disorders (LPDs), 16 LPDs (nine mature T-cell neoplasms, seven mature B-cell neoplasms and immune dysregulation–associated LPDs), and four atypical LPDs from 22 females and 19 males with a median age of 58 (range, 9-87) years. (1) NGS analyzed TRG sequence and peak ratios, and it had a greater sensitivity than PCR. (2) NGS identified small clones, including biallelic or monoallelic, and minimum clonal percentages (range, ~2.4% to ~69%) within all T cells. (3) We provide our strategy and criteria for evaluating NGS results. (4) We describe every case, with definitive evaluation of TRG clonality in 100% cases by NGS. TRG clonality evaluation by NGS provides greater clinical utility than PCR.