GENETIC AND EPIGENTIC CHANGES IN ACUTE MYELOID LEUKEMIA
Acute myeloid leukemia (AML) is a molecularly heterogeneous cancer of hematopoietic cells. Several genetic changes alter normal hematopoietic growth and differentiation in AML, causing large numbers of abnormal, immature myeloid cells to accumulate in the bone marrow and peripheral blood. These cells can divide and proliferate, but they can’t differentiate into mature hematopoietic cells. Recurrent structural alterations of chromosomes serve as the established diagnostic and prognostic markers in AML.
What Sequencing Studies Have Found
Several studies using targeted sequencing (determining the DNA sequence of specific areas of interest within the genome) identified recurrent gene mutations that carry diagnostic and prognostic information, including mutations in the FLT3, NPM1, KIT, CEBPA, and TET2 genes. In addition, massively parallel sequencing (a high-throughput DNA sequencing approach, also called next-generation sequencing) has uncovered recurrent mutations in the DNMT3A and IDH1/2 genes that may also provide prognostic information for some patients.
Even though these genetic abnormalities may play an essential role in AML’s pathogenesis, nearly 50% of AML patients have a normal karyotype (an organized profile of a person’s chromosomes). Based on cytogenetic analysis, doctors classify AML patients into three major risk categories: favorable, intermediate, and unfavorable. Patients with PML-RARA, RUNX1-RUNX1T1, or MYTH11-CBFB gene fusions (resulting from chromosomal rearrangements) fall into the favorable-risk category and tend to respond relatively well to chemotherapy. Patients with complex genetic alterations (such as monosomy karyotype) fall into the unfavorable-risk profile. Most AML patients have a normal karyotype and fall into the intermediate-risk category — some respond well to chemotherapy, and others don’t.
Since nearly 50% of AML patients have a normal chromosomal profile, better molecular characterization of AML’s pathogenesis is needed to improve treatment approaches. Next-generation sequencing (NGS) studies have also revealed that even though AML tumors usually harbor hundreds of mutated genes, only a limited number of these mutations actually serve as driver mutations (meaning they cause the tumor). Among the adult cancer types sequenced extensively so far, AML has had the fewest mutations discovered. Identifying more novel driver mutations that occur at low frequency in AML will help researchers better understand leukemogenesis.
A Landmark Genomic Study
A study recently published in the New England Journal of Medicine (May 1st, 2013) by researchers at The Cancer Genome Atlas (TCGA) group, led by Timothy J. Ley, broadly classified the genomic alterations that frequently underlie AML’s development. This study also suggested potential new drug targets and treatment strategies for AML. The researchers analyzed the genomes of 200 newly diagnosed adult AML patients representing all known subtypes, performing whole-genome sequencing on 50 cases and whole-exome sequencing on 150 cases. They also performed RNA and micro-RNA sequencing, along with DNA-methylation analysis.
The researchers compared each AML genome to the normal genome derived from a skin sample of the same patient. They grouped the recurrently mutated genes discovered in this study into nine categories, defined by biologic function, that are thought to play a role in AML pathogenesis. These groups include tumor suppressor genes, transcription-factor fusions, activated signaling genes, and epigenetic modifiers (DNA-methylation related genes and chromatin-modifying genes) — with epigenetic modifiers being the most frequently mutated class of genes found in the study. The researchers identified at least one potential driver mutation in nearly all AML samples, including genes already well established as associated with AML pathogenesis (such as FLT3, NPM1, DNMT3A, IDH1, IDH2, and CEBPA).
This study was also the first to observe recurrent mutations in cohesin genes, which play an important role in cell division, appearing in 13% of AML samples. In addition, the researchers observed a mutation in microRNA 142 (miR-142). Overall, this study provided a detailed understanding of the genetic and epigenetic changes associated with adult de novo AML. Future studies are needed to understand how these alterations relate to treatment outcomes.
References:
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4. Network TCGAR. Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. N Engl J Med. 2013.
