microRNA Prognostic Marker Identified in Acute Leukemia
CLARA D. BLOOMFIELD, MD,
Distinguished University Professor, the William Greenville Pace III Endowed Chair in Cancer Research, and cancer scholar/senior adviser to the OSUCCC – James
A study led by researchers at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James) has identified microRNA-3151 as an independent prognostic marker in certain patients with acute leukemia.
Revised Classification Should Improve Patient Care
The study involved patients with acute myeloid leukemia and normal-looking chromosomes (CN-AML). It found that when microRNA-3151 (miR-3151) is overexpressed in CN-AML, the disease responds poorly to treatment, and patients experience shorter remissions and survival periods.
This effect is independent of other gene mutations that may be present. Additionally, miR-3151 is encoded within a gene called BAALC, which itself is an independent marker of poor survival when overexpressed in CN-AML.
The findings provide insight into the nature of AML and might help determine the best therapy for individual patients, further personalizing AML therapy.
"Patients with high levels of both miR-3151 and BAALC had the poorest outcome compared with those showing high expression of
either miR-3151 or BAALC alone, or those expressing low levels of both," says principal investigator Clara D. Bloomfield, MD, a Distinguished University Professor and cancer scholar/senior adviser to the OSUCCC – James. "This suggests that miR-3151 and BAALC may act through different mechanisms to enhance poor outcome of CN-AML patients."
The study involved 179 patients of age 60 or older with CN-AML who were treated on Cancer and Leukemia Group B (CALGB) clinical trials.
MicroRNAs are small molecules that cells use to help regulate the kind and amount of proteins they make. About a third of human microRNAs are encoded within host gene sectors called introns, short stretches of DNA that are not used when genetic information is translated to make a protein.
First author Ann-Kathrin Eisfeld, MD, a postdoctoral researcher in the laboratory of study co-author Albert de la Chapelle, MD, PhD, and Bloomfield, says this study provides "the first description of interplay of an oncogene and its intronic, and possibly oncogenic, microRNA."
Published in the Journal Blood
ARNAB CHAKRAVARTI, MD,
professor and chair of the Department of Radiation Oncology, co-director of the Brain Tumor Program at the OSUCCC – James and the Max Morehouse Chair in Cancer Research
Radiation oncology researchers have revised the system used by doctors since the 1990s to determine the prognosis of people with glioblastoma, the most devastating of malignant brain tumors.
The outdated system, which was devised for glioblastoma and related brain tumors that were treated by radiation therapy only, relied on clinical signs and symptoms, and it divided patients into six prognostic groups. The new system accommodates advances in treatment, particularly the use of radiation therapy plus the chemotherapy drug temozolomide, and incorporates molecular biomarkers as well as clinical variables.
"The new model is more relevant and contemporary, and it should do a better job of identifying patients who require the most aggressive therapy," says Arnab Chakravarti, MD, the study's chair for translational research.
Chakravarti, professor and chair of the Department of Radiation Oncology at Ohio State and co-director of the Brain Tumor Program at the OSUCCC – James, presented study findings at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
To devise the new system, Chakravarti and colleagues compared tumor and healthy tissue from 162 glioblastoma patients who were treated under the Radiation Oncology Group clinical trial 0525 (RTOG 0525). The investigators profiled protein, messenger RNA and epigenetic changes in patients' tumor cells while looking for alterations in key signaling molecules.
They showed that high expression of the proteins pAKT, c-met and MGMT was associated with poor prognosis, while methylation of the MGMT gene, which codes for a DNA repair protein, was associated with a better prognosis.
"We hope to begin further studies to validate our classification system soon," Chakravarti says.
To refer a patient, please call The James Line New Patient Referral Center toll free: 1-800-293-5066.
Inherited DNA Alteration Explains Overactive Leukemia Gene
ALBERT DE LA CHAPELLE,
co-leader of the Molecular Biology
and Cancer Genetics Program and the
Leonard J. Immke, Jr. and Charlotte L.
Immke Chair in Cancer Research Fund
A new study shows that a small inherited change in DNA is largely responsible for overactivating a gene linked to poor treatment response in people with acute leukemia.
The study, led by researchers at the OSUCCC – James, focused on the BAALC gene, which is often overexpressed in acute myeloid or acute lymphoblastic leukemia. This work indicates that these diseases
will likely respond poorly to standard therapy.
Researchers discovered that BAALC overexpression is caused by a small change called a single nucleotide polymorphism (SNP) in the gene's DNA. The SNP alters the gene's "on" switch, allowing a different molecule to keep it "running" when it shouldn't.
"This SNP doesn't raise risk of developing leukemia, but it predisposes to overexpression of the BAALC gene, which is associated with leukemia development and poor response to treatment," says principal
investigator Albert de la Chapelle, MD, PhD, co-leader of the Molecular Biology and Cancer Genetics Program at the OSUCCC– James.
The findings suggest this SNP could be a useful prognosis marker and help guide therapy in acute leukemia patients.
Researchers say the DNA change caused by the SNP creates a binding site for an activating molecule called RUNX1, which is also involved in forming normal and malignant blood cells. The scientists showed that patients with high levels of RUNX1 protein also had high BAALC expression, while those with low RUNX1 protein had low BAALC gene expression.
For this study, de la Chapelle and colleagues used DNA sequencing to examine the genomic region of BAALC in 253 patients with cytogentically normal AML treated in Cancer and Leukemia Group B clinical trials. The analysis revealed nine SNPs of interest, but the researchers focused only on one called rs62527607[T].
"We doubt that this SNP is entirely responsible for BAALC overexpression, but we believe it is a major contributor," de la Chapelle says.
Published in Proceedings of the National Academy of Sciences.
Supported in part by NIH/National Cancer
Institute grants CA098933, CA101140,
CA114725, CA140158, CA31946,
CA33601, CA16058, CA77658, and
Marker Distinguishes Aggressive Form of Chronic Leukemia
JOHN C. BYRD, MD,
director of the Division of Hematology; professor of Medicine, of Medicinal Chemistry and of Veterinary Biosciences; and the D. Warren Brown Designated Chair in Leukemia Research
Researchers have identified a prognostic marker in the most common form of chronic leukemia that can help distinguish patients who should start treatment quickly from those who can safely delay treatment, perhaps for years.
The study, led by researchers at the OSUCCC – James, focused on chronic lymphocytic leukemia (CLL). Examining a gene called ZAP-70 in CLL cells for a chemical change called methylation, they found that, when this gene in leukemia cells is methylated, patients are likely to have the slowprogressing form of CLL. When the ZAP-70 gene is unmethylated, patients are likely to have aggressive disease and should consider immediate treatment.
Currently, doctors must simply observe newly diagnosed patients to determine which type of CLL they have. This can delay the start of treatment in patients with aggressive disease, or it can lead to treating patients who don't yet require it.
"This study demonstrates that ZAP-70 methylation status is a highly predictive, reproducible biomarker of poor prognosis in this disease, and a clinically useful prognostic test for CLL," says principal investigator John C. Byrd, MD, a CLL specialist who directs the Division of Hematology at Ohio State.
The presence of mutations in a gene called IGVH and the amount of protein produced by the ZAP-70 gene in CLL cells are sometimes used to predict prognosis and response to treatment in people with this disease, "but these assays are expensive and difficult to perform," says study co-author and researcher David Lucas, PhD.
"In all cells, some areas of DNA undergo methylation, which controls how that DNA is used," Lucas says. "In cancer cells, the pattern of DNA methylation is often different from that of healthy cells, and this influences how much protein is produced by ZAP-70 and other genes."
Published in the Journal of Clinical Oncology
LEUKEMIC MECHANISM UNMASKED
microRNA Loss May Power Malignant Transformation in CLL
CARLO CROCE, MD,
director of Human Cancer Genetics and the John W. Wolfe Chair in
Human Cancer Genetics
Loss of a particular microRNA in chronic lymphocytic leukemia shuts down normal cell metabolism and turns up alternative mechanisms that enable cancer cells to produce the energy and build the molecules they need to proliferate and invade neighboring tissue.
The findings come from a study led by researchers at the OSUCCC – James, who showed that microRNA-125b (miR-125b) by itself regulates many enzymes and other molecules that allow cells to make building blocks for their growth and proliferation, such as DNA and lipids needed for cell membranes.
The study also showed that miR-125b is often lost in chronic lymphocytic leukemia (CLL), and that the loss is associated with higher rates of glucose metabolism. This is a characteristic of cancer cells called the Warburg effect, and it alters how cancer cells use glucose to generate energy. This finding suggests that loss of miR-125b is an early step in CLL development.
The researchers say the study provides a more comprehensive understanding of how cancer develops and identifies potential targets for CLL drug development.
"Our findings indicate that miR-125b is downregulated in both aggressive and indolent forms of CLL, and that this downregulation is associated with metabolic adaptation to cancer transformation," says principal investigator and corresponding author Carlo Croce, MD, director of Human Cancer Genetics at Ohio State and a member of the OSUCCC – James Molecular Biology and Cancer Genetics Program.
"By identifying the metabolites that are changed, as we have here, we can propose to use drugs that target them and perhaps control the leukemia," Croce says.
Scientists have known for some time that, as normal cells become cancerous, different metabolic pathways are switched on and support the enhanced growth and energy needs of malignant cells. This study reveals one way that can happen.
Published in the journal Blood.
People With Allergies May Have Lower Risk of Brain Tumors
JUDITH SCHWARTZBAUM, PhD,
a member of the OSUCCC – James Cancer Control Program and the study's lead author
An Ohio State University study adds to growing evidence that links allergies and reduced risk of a type of brain cancer. The study suggests the reduced risk is stronger among women than men, but men with certain allergy profiles also have a lower tumor risk.
Because these tumors, called gliomas, can suppress the immune system to allow themselves to grow, researchers have never been sure whether allergies reduce cancer risk or if, before diagnosis, these tumors interfere with the hypersensitive immune response to allergens.
In this study, scientists analyzed stored blood samples taken from patients decades before they were diagnosed with glioma. Men and women whose blood samples contained allergy-related antibodies had an almost 50-percent lower risk of developing glioma 20 years later compared with people without signs of allergies.
"This is our most important finding," says Judith Schwartzbaum, PhD, a member of the OSUCCC – James Cancer Control Program and the study's lead author. "The longer before glioma diagnosis that the effect of allergies is present, the less likely it is that the tumor is suppressing allergies."
The researchers analyzed stored blood samples from 594 people in Norway who were diagnosed with glioma (including 374 with glioblastoma) from 1974-2007, then compared them – for date of blood collection, age and sex – with 1,177 samples from people not diagnosed with glioma.
They next measured levels of two types of proteins called IgE, or immunoglobulin E – antibodies produced by white blood cells that mediate immune responses to allergens. In each sample, they determined whether the serum contained elevated levels of IgE specific to common allergens in Norway, as well as total IgE.
Among women, testing positive for elevated allergen-specific IgE was associated with a 54-percent decreased risk of glioblastoma compared with women who tested negative for allergen-specific IgE. The researchers did not see this association in men.
"There is definitely a difference in the effect of allergen-specific IgE between men and women," Schwartzbaum says.
Published in the Journal of the National Cancer Institute