Investigators at St. Jude
Children's Research Hospital have discovered previously unsuspected
mutations that contribute to the formation of pediatric acute lymphoblastic
leukemia (ALL), the most common cancer in children. The discovery not only
suggests novel methods for treating pediatric ALL, but also provides a
roadmap for the identification of unsuspected mutations in adult cancers.
The St. Jude team used microarrays, postage-stamp-sized chips that
contain DNA fragments, which allowed researchers to investigate more than
350,000 markers called single nucleotide polymorphisms. Single nucleotide
polymorphisms are individual variations in the DNA that are spaced across
the human chromosomes. Single nucleotide polymorphisms function as flags
for researchers, allowing them to detect specific deletions of DNA in a
gene or increases in the number of specific genes at a level of detail that
was previously unattainable. The St. Jude group used this approach to
analyze leukemia samples from 242 pediatric patients with ALL. This
identified an unexpectedly high frequency of mutations involving genes that
function as master regulators of normal B-cell development and
differentiation.
A report on this work appears in the March 7 online edition of
"Nature."
"The results of our study demonstrate that it is possible to
significantly speed the identification of the genetic lesions that are the
underlying cause of not only ALL, but also many other cancers, including
those affecting adults," said James Downing, M.D., scientific director and
chair of the Pathology department at St. Jude. He is senior author of the
paper.
The study found that 40 percent of patients with ALL had deletions or
mutations in one of three so-called "master genes" that control the normal
differentiation of immature progenitor cells into mature B lymphocytes. In
ALL, the leukemic cells fail to differentiate normally and remain blocked
at an immature stage of development. Locked in this state, the leukemic
cells continue to proliferate, and this continual growth of leukemic cells
eventually kills the child. The mutations identified in three genes,
"PAX5," "EBF" and "Ikaros," are likely to directly contribute to this block
in normal lymphocyte differentiation.
"The more we learn about why progenitor cells get stuck in the
primitive, cancerous stage, the more likely we'll be able to design new
therapies that eliminate them. That could help us continue our successful
efforts to increase the survival rate of ALL," said Ching-Hon Pui, M.D.,
chair of the Oncology department and American Cancer Society Professor at
St. Jude. Pui co-authored the paper.
The other authors of this paper include William E. Evans, Mary V.
Relling, Charles G. Mullighan, Salil Goorha, Ina Radtke, Christopher B.
Miller, Elaine Coustan-Smith, James D. Dalton, Kevin Girtman, Susan Mathew,
Jing Ma, Stanley B. Pounds, Xiaoping Su and Sheila A. Shurtleff.
This work was supported in part by the National Cancer Institute, the
National Institute of General Medical Sciences, the National Health and
Medical Research Council (Australia), the Royal Australasian College of
Physicians, the Haematology Society of Australia and New Zealand, and
ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for
its pioneering work in finding cures and saving children with cancer and
other catastrophic diseases. Founded by late entertainer Danny Thomas and
based in Memphis, Tenn., St. Jude freely shares its discoveries with
scientific and medical communities around the world. No family ever pays
for treatments not covered by insurance, and families without insurance are
never asked to pay. St. Jude is financially supported by ALSAC, its
fundraising organization. For more information, please visit
stjude.
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