Acute lymphoblastic leukemia (ALL) is a cancer that starts from the lymphocytes in the bone marrow. It occurs most often in children who are between three and five years
old.


A new, high-risk subtype
of acute lymphoblastic leukemia (ALL) as well as a possible targeted
therapy has been uncovered by an international research team led by St. Jude Children’s Research
Hospital. The findings appear today in the scientific journal Nature Communications.

‘A new, high-risk subtype of acute lymphoblastic leukemia (ALL) as well as a possible targeted therapy has been uncovered by an international research team.’

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The subtype is characterized by chromosomal rearrangements that
involve the MEF2D gene and one of six partner genes, most often the gene
BCL9. It is called MEF2D-rearranged ALL.

“MEF2D is a transcription factor that switches on expression of
other genes during normal development,” said corresponding author
Charles Mullighan, a member of the St. Jude Department of
Pathology. “We found that MEF2D chromosomal rearrangements disrupt
expression of those genes and create a vulnerability to at least one
targeted therapy, the drug panobinostat.”

Genomic analysis of more than 1,700 children, adolescents and adults
with ALL identified 42 with MEF2D rearrangements. Researchers
calculated that MEF2D-rearranged ALL accounts for 5.3% of the
almost 30% of ALL cases whose genetic basis was unknown. The
MEF2D-rearranged subtype occurred most frequently in adolescents and was
associated with reduced survival compared to some other ALL subtypes.

Panobinostat inhibits the activity of a family of proteins including
HDAC9. Researchers showed that MEF2D-rearranged leukemic cells produced
high levels of HDAC9. Investigators tested panobinostat in the
laboratory and found the drug stopped proliferation of human
MEF2D-rearranged leukemic cells.

Panobinostat and similar drugs are known to have broad anti-tumor
activity and are currently being tested in therapies for different types
of leukemia and lymphoma. Mullighan said MEF2D-rearranged leukemic
cells were exquisitely sensitive to panobinostat, which suggested the
drug might function in a more targeted manner against cells with the
rearrangement.

“If further testing of panobinostat, either alone or in combination
therapy, confirms the anti-proliferative activity that would lay the
foundation for a clinical trial in patients, particularly patients with
high-risk disease or those who have relapsed,” he said.

For this study, researchers sequenced the RNA of 560 ALL patients to
discover genetic changes, particularly chromosomal rearrangements that
drive tumor growth. The findings were verified by RNA sequencing of
1,164 cases.

Two cases also underwent whole genome sequencing (WGS). WGS examines
the sequence of DNA that encodes the complete set of instructions
needed for life. RNA sequencing provides a snapshot of which genes in
the genome are being expressed and the level of their expression. This
method of next-generation sequencing is particularly suited for
identifying novel gene rearrangements, including fusion genes created
when pieces of genes break and fuse when chromosomes break and
reassemble.

The leukemia samples used in this study came from patients in the
U.S., Canada and Europe, including the federally funded Children’s
Oncology Group (COG) and eight other institutions and research
cooperatives. The research involved collaboration with the National
Cancer Institute’s Therapeutically Applicable Research to Generate
Effective Treatments (TARGET) Initiative. TARGET uses genomic analysis
of COG samples to identify therapeutic targets and spur development of
more effective treatment for childhood cancer.

“Over the past decade we have learned a great deal about the genetic
changes that lead to development of ALL,” said co-author Stephen
Hunger of the Children’s Hospital of Philadelphia and the
Perelman School of Medicine at the University of Pennsylvania, and
director of the TARGET/COG ALL project. “However, as this study shows,
we continue to identify new subsets of ALL defined by specific genetic
changes in the leukemia cells that often provide important information
about treatment outcome and identify new strategies for precision
medicine treatments.”

In addition to patients with the MEF2D-rearranged subtype,
researchers also identified 20 patients with chromosomal rearrangements
that involved the ZNF384 gene and one of six different partner genes.
Both the cases with MEF2D and ZNF384 rearrangements had distinct
patterns of gene expression, suggesting the fusions are key drivers of
each type of ALL.

Researchers also showed a fusion protein resulting from the
MEF2D-rearragement led to sustained growth of mouse cells in the
laboratory compared to the normal MEF2D or other proteins. “That
indicates the MEF2D fusion is a key step in transforming a normal white
blood cell with a finite lifespan into a leukemic cell that is
immortal,” Mullighan said.

Laboratory and clinical findings identified other distinctions. The average patient with MEF2D-rearranged ALL in this study was
14.The five-year cancer-free survival for MEF2D-rearranged ALL patients
was 71.6%. That is better than some high-risk ALL subtypes, but
it lagged behind the 87.3% for patients with certain other
high-risk ALL subtypes.

Source: Eurekalert



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