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.