A team of investigators led by scientists at St. Jude Children's Research Hospital and the Washington University Pediatric Cancer Genome Project (PCGP) has published a comprehensive map of the genomic landscape for the form of acute myeloid leukemia (AML) called core-binding factor acute myeloid leukemia (CBF-AML). This new work reveals differences in mutations that contribute to the diversity of CBF-AML—the findings of which were published recently in Nature Genetics through an article entitled “The genomic landscape of core-binding factor acute myeloid leukemias.”
"We set out to understand the genetic variations that contribute to the development of CBF-AML using whole-exome and whole-genome sequencing," explained co-lead study investigator Jeffery Klco, M.D., Ph.D., assistant member of the St. Jude department of pathology. "Our goal was to define a detailed mutational landscape to understand better the genetic changes that contribute to disease."
CBF-AML accounts for approximately 30 percent of pediatric AML and 15 percent of adult cases. The researchers were able to obtain and sequence samples from 87 children and 78 adults and found a similar mutational landscape in both groups. Moreover, in 17 cases, whole genome sequences (WGS) were obtained, while whole-exome sequencing (WES) was carried out on the remaining 148 samples.
Researchers have been cognizant for some time that two genes—RUNX1 and CBFB—can be affected by chromosomal rearrangements in AML. These genes encode for proteins that are part of the core-binding factor (CBF) complex, a transcriptional complex essential for normal blood cell development. CBF-AML arises by chromosomal rearrangements that impair the activity of the CBF complex.
While patients with CBF-AML have a massive accumulation of abnormal cells known as myeloid blasts and an acute shortage of mature blood cells, these chromosomal rearrangements are not sufficient for the development of cancer. This phenomenon has prompted scientists to search for other mutations that can work together with the genetic rearrangements to cause leukemia.
"One or more cooperating mutations are needed for leukemia to take hold," Dr. Klco noted. "Our analysis showed dramatic differences in the genetic landscapes of these cooperative mutations for CBF-AML with rearrangements involving RUNX1 compared to those that involve CBFB."
Interestingly, the researchers identified several mutations that may contribute as cooperating mutations, including changes in CCND2, a gene that makes a protein involved in the cell cycle. New recurrent mutations were also identified, including alterations in DHX15, which has a role in modifying certain types of RNA.
"Mutations that shortened the length of CCND2 were clustered around one end of the protein, the C-terminus, and resulted in stabilization of cyclin D2 and cell cycle activation” stated co-study author Jinghui Zhang, Ph.D., chair of the St. Jude department of computational biology. "Many of the mutations we identified interfered with molecular signaling or epigenetic factors."
Other genes identified that might contribute to CBF-AML included ASXL2, ZBTB7A, and MGA. "Some of the mutations, like ASXL2, are epigenetic regulators that modify the local state of chromatin. Others, like ZBTB7A, appear to act as tumor suppressors," Dr. Klco said.
Patients with CBF-AML have a relatively good prognosis. However, the disease recurs in some patients. "In some cases, we were also able to look at the types of mutations in CBF-AML at diagnosis and relapse to understand how the disease changes over time, and we hope to build on this work moving forward," Dr. Klco added.
"This study highlights how the Pediatric Cancer Genome Project continues to generate new insights into genetic alterations and cooperating mutations that give rise to diseases like AML," stated co-senior study investigator James Downing, M.D., St. Jude president and chief executive officer. "The results suggest some new components that may have a functional role in CBF-AML and also highlight genes that may be crucial for patients at risk of relapse."