Abnormal gene found to be cause of rare childhood leukemia
14 November 2012
An international team led by the St. Jude Children's Research
Hospital - Washington University Pediatric Cancer Genome Project has
identified a fusion gene responsible for almost 30% of a rare subtype of
childhood leukemia with an extremely poor survival rate.
The finding offers the first evidence of a genetic mistake that
gives rise to a significant percentage of acute megakaryoblastic
leukemia (AMKL) cases in children. AMKL accounts for about 10%of
pediatric acute myeloid leukemia (AML). The discovery paves the way
for desperately needed treatment advances.
Source of genetic mistake
Investigators from the US, Italy, Germany, Japan and Taiwan
traced the genetic misstep to the rearrangement of chromosome 16,
which brings together pieces of two genes and sets the stage for
production of an abnormal protein. The fusion protein features the
front end of CBFA2T3, a blood protein, and the back of GLIS2, a
protein that is normally produced only in the kidney. Work that
appears in the November 13 edition of the journal Cancer Cell
reports that in a variety of laboratory models the CBFA2T3-GLIS2
protein switched on genes that drive immature blood cells to keep
dividing long after normal cells had died. This alteration directly
contributes to leukemia.
AMKL patients with the fusion gene were also found to be at high
risk of failing therapy. Researchers checked long-term survival of
40 AMKL patients treated at multiple medical centres around the
world and found about 28% of patients with the fusion gene became
long-term survivors, compared to 42% for patients without
CBFA2T3-GLIS2. Overall long-term survival for pediatric AML patients
in the U.S. is now 71%.
Improved diagnostic testing
"The discovery of the CBFA2T3-GLIS2 fusion gene in a subset of
patients with AMKL paves the way for improved diagnostic testing,
better risk stratification to help guide treatment and more
effective therapeutic interventions for this aggressive childhood
cancer," said James Downing, M.D., St. Jude scientific director and
the paper's corresponding author. The first author is Tanja Gruber,
MD, PhD, an assistant member in the St. Jude Department of Oncology.
Co-author Richard Wilson, PhD, director of The Genome Institute
at Washington University School of Medicine in St. Louis, noted: "We
identified this unusual gene fusion by comparing the genome of
children's healthy cells with the genome of their cancer cells. This
type of in-depth exploration and analysis is crucial to finding
unexpected structural rearrangements in the DNA that can lead to
cancer. With this discovery, we now can search for more effective
treatment options that target this precise defect."
The study is part of the Pediatric Cancer Genome Project, a
three-year collaboration between St. Jude and Washington University
to sequence the complete normal and cancer genomes of 600 children
and adolescents with some of the most aggressive and least
understood cancers. The human genome is the instruction book for
assembling and sustaining a person. The instructions are packaged in
the DNA molecule. Sequencing the genome involves determining the
exact order of the four chemical bases that make up DNA. Human DNA
is organized into 46 chromosomes.
"We focused on AMKL because no one had any idea of what caused
this leukemia in most patients," Gruber said. The study excluded
AMKL patients who were infants or children with Down syndrome
because earlier research had linked their disease to other
When researchers in this study sequenced just the genes that were
switched on in the AMKL cells of 14 young patients, the scientists
discovered half carried the CBFA2T3-GLIS2 fusion. Additional fusion
genes were identified in five of the other patients. Each of those
fusion genes occurred in a single patient. The genes involved
included HOXA9 and MN1, both previously linked to leukemia, and
GATA2 and FLII, which play roles in normal development of the
megakaryocytic blood cells that are targeted in AMKL. Megakaryocytes
produce the platelets that help blood clot.
Additional sequencing of DNA from adult and pediatric AMKL
patients, including whole genome sequencing of the normal and cancer
cells of four young AMKL patients, found the CBFA2T3-GLIS2 protein
was unique to pediatric AMKL. Of the 48 pediatric AMKL patients
screened in this study, 13 carried the fusion gene. None of 28 adult
AMKL patients screened had the gene.
"Whole genome sequencing has allowed us to detect alterations in
cancer cells that were previously unknown. Many of these changes
contribute directly to the development of cancer," Gruber said.
"Such sequencing also provides the deeper understanding of the
disease that is critical for developing more effective, less-toxic
GLIS2 is a transcription factor, meaning it attaches to DNA and
turns genes on or off. GLIS2 is normally switched off in blood cells
and has not been previously linked to cancer.
Working in several laboratory models, researchers showed that
GLIS2, either alone or in the fusion gene, increased the activity of
other genes in pathways that control cell functions disrupted in
cancer. The genes include BMP2 and BMP4, which are now the focus of
additional research. The genes are in a pathway that is active early
in the developing blood system. This study implicated the genes in
Gruber TA, et al. An inv(16)(p13.3q24.3)-encoded
CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of
pediatric acute megakaryoblastic leukemia. Cancer Cell.
Online November 12, 2012; Issue November 13, 2012