Taken together, these findings supported the fact that AML phenotype is driven by underlying mutational signature ( Figure 1).Īccordingly, both the 2016 revisions to the WHO and 2017 European LeukemiaNet ( 5) incorporated gene mutations into the sub-classification and risk-stratification of AML ( 6, 7). The additional separate categories included AML with mutations in genes encoding chromatin and RNA-splicing regulators, AML with TP53 mutations and/or chromosomal aneuploidies, and AML with IDH2 R172 mutations ( 4). In 2016, a large cohort that enrolled 1540 AML patients described 11 subgroups of genomic alterations with different clinical outcomes using NGS. An average of 14 mutations were identified in the AML genome, ranging between five to 23 genetic mutations in each case ( 3).
In 2013, the Cancer Genome Atlas (TCGA) project expanded the functional genetic classes to nine families involved in the pathogenesis of the myeloid neoplasms. The development of high-throughput NGS sequencing platforms uncovered many somatic mutations in AML. Prior to 2008, there were two functional genetic groups for leukemic pathogenesis: class I (activated signaling genes such as FLT3, KIT and RAS mutations) that conferred the proliferative potential, and class II genes involved in transcription and differentiation such as CEBPA and RUNX1 ( 2). Mutation profiling is standard for routine baseline clinical evaluation of AML. In this review, using a few prototypic genes in AML, we will summarize the clinical applications of NGS generated data for optimal AML management, with emphasis on the recently described entities and Food and Drug Administration approved target therapies.Īcute myeloid leukemia ( 1) is a clonal malignant expansion of immature myeloid precursors due to block in differentiation.
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These include identification of evidence regarding the ontogeny of the disease, underlying germline predisposition and clonal hematopoiesis, serial monitoring to assess the effectiveness of therapy and resistance mutations, which have broader implications for management. In addition, there is a vast amount of informative data that can be obtained from routine clinical NGS sequencing beyond diagnosis, prognostication and therapeutic targeting. Hence, molecular mutational profiling is an integral component for work-up of AML and multiple leukemic entities. NGS mutation profiling provides a large amount of information that guides diagnosis and management, dependent on the type and number of gene mutations, variant allele frequency and amenability to targeted therapeutics. These findings urged incorporation of molecular results into the latest World Health Organization (WHO) sub-classification and integration into risk-stratification and treatment guidelines by the European Leukemia Net. The extensive application of NGS in hematologic malignancies, and its significant association with the outcomes in multiple large cohorts constituted a proof of concept that AML phenotype is driven by underlying mutational signature and is amenable for targeted therapies. Next generation sequencing (NGS) is routinely used for mutation profiling of acute myeloid leukemia. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.Hanadi El Achi and Rashmi Kanagal-Shamanna *
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