July 14, 2004 The results of a microarray analysis of genes from both children and adults with acute myeloid leukemia (AML) could significantly improve the ability to make accurate diagnoses and prognoses for the major genetic (molecular) subtypes of the pediatric form of this disease and lead to better treatments. This finding, by investigators at St. Jude Children's Research Hospital, is published in the journal Blood.
AML is a cancer that arises in bone marrow hematopoietic stem cells (HSCs) or progenitor cells that are destined to become myeloid cells (cells normally committed to fighting infections). Gene microarray technology uses small chips containing gene "probes" to measure the level of expression of thousands of specific genes simultaneously by using samples of genetic material obtained from normal or diseased cells. HSCs are parent cells in the bone marrow that can potentially give rise to any one of the various types of blood cells. Progenitor cells are those that have arisen from HSC and are committed to producing a specific type of blood cell.
The study of children and adults found that leukemic cells of each major known prognostic subtype of AML had a specific "signature" of gene expression. The exact signature depended on the underlying genetic mutation that contributed to the formation and growth of the leukemic cells; and it corresponded to over- or under-expression of sets of genes from leukemic cells as compared to their expression in normal white blood cells. Prognostic subtypes are categories of different forms of AML that are recognized because they tend to have known, predictable outcomes following treatment.
Importantly, this study also demonstrated that the gene expression signatures identified in the pediatric leukemias could also be used to accurately diagnose the identical form of leukemia when it occurs in adults. Thus, insights gained from pediatric AML, which is a relatively rare disease, should rapidly lead to improved understanding of adult AML, which occurs at a much higher incidence.
The identification of AML subtype signatures is important because the outlook for a particular patient depends on whether he or she has the subtype that is favorable, intermediate or unfavorable, according to James Downing, M.D., chair of the St. Jude department of Pathology and co-leader of its Hematological Malignancies program. For example, the subtype PML-RAR-á has a favorable prognosis, while other subtypes have a poorer prognosis.
Downing is senior author of the Blood report.
"The gene expression signatures will also give us insights into the causes of each subtype of AML, which is an important step toward developing new and more effective treatments," he says.
Another discovery was that an expression signature could be identified for a subtype of AML, which results from a mutation in the MLL chimeric fusion gene regardless of which type of white blood cell gave rise to it. A partial duplication of the MLL gene resulted in a completely different gene signature than the one caused by the MLL chimeric fusion gene. This suggests that the two different mutations of the same gene cause AML by two different mechanisms.
"Our ability to make such fine distinctions among the various subtypes of AML based on gene expression signatures is much like developing a dictionary," Downing said. "In this case, one gene expression signature defines a person as having a specific subtype of AML, while a person with another signature has a different type of AML."
Knowing which subtype of AML a patient has makes it easier to determine the best treatment and that treatment's chance of success, according to Downing. "This study will also contribute to our understanding of the various underlying causes of AML. In other words, it will help take a lot of the educated guesswork out of managing AML," he said.
Other authors of this paper are Mary E. Ross, Rami Mahfouz, Mihaela Onciu, His-Che Liu, Xiaodong Zhou, Guangchun Song, Sheila A. Shurtleff, Stanley Pounds, Cheng Cheng, Jing Ma, Raul C. Ribeiro, Jeffrey E. Rubnitz, Kevin Girtman, W. Kent Williams, Zusana C. Raimondi, and Ching-Hon Pui (St. Jude); Der-Cherng Liang (Mackay Memorial Hospital, Taipei, Taiwan); and Lee-Yung Shih (Chang Gung Memorial Hospital, Taipei, Taiwan).
### This work was supported in part by the National Cancer Institute, the St. Jude Physician Scientist Training Program 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, Tennessee, 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 http://www.stjude.org.
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