St. Jude identifies genomic causes of a certain type of leukemia relapse

December 01, 2008

New study finds the majority of acute lymphoblastic leukemia relapse cases arise from a cell already present at the time of diagnosis

Scientists at St. Jude Children's Research Hospital have identified distinctive genetic changes in the cancer cells of children with acute lymphoblastic leukemia (ALL) that cause relapse. The finding offers a pathway to designing treatments for ALL relapse in children and, ultimately, in adults.

The most common childhood cancer, ALL affects thousands of children annually in the United States. Although more than 80 percent of ALL cases are cured, relapse is a significant problem, with only 30 percent of children with relapsed ALL surviving.

Previous studies had found some evidence for genetic differences between the cancer cells of ALL patients at initial diagnosis and those who relapsed. That information was limited, and there had never been a broad comparison of the entire genomes of ALL at initial diagnosis and at subsequent relapse.

In the study that appears in the Nov. 28, 2008, issue of the journal Science, St. Jude researchers compared the genomes of the cancer cells of 61 childhood ALL patients when they were initially diagnosed and after they had relapsed. The investigators used millions of genetic markers-characteristic genetic variations called single nucleotide polymorphisms-as guideposts to pinpoint genetic changes characteristic of relapsed cells. Using these genetic markers, the researchers analyzed all of the cells' chromosomes to look for genetic changes called copy number abnormalities specific to relapsed cells. These changes are considered a major type of damaging gene alterations in ALL.

"In more than 90 percent of the cases, we found differences in the genetic alterations present at the time of diagnosis and at the time of relapse," said Charles Mullighan, M.D., Ph.D., assistant member in the St. Jude Department of Pathology and the paper's first author. "Examining the new changes that are arising at relapse tells us a lot about the individual genetic lesions that might confer resistance to treatment and be responsible for relapse."

According to the researchers, the relapse-related genetic changes commonly disrupted the machinery by which white blood cells called B cells mature and proliferate. Importantly, the relapse-related genetic changes only infrequently involved genes directly regulating the responsiveness to anti-cancer drugs.

The analysis also indicated that in most cases, the cancer cells responsible for relapse were related to those that originally gave rise to the cancer. Those relapse cells were present at low levels at diagnosis, the scientists' analysis indicated. However, in a few cases, the relapse cells evolved from genetically distinct cells, indicating that the relapsed leukemia was actually an entirely new cancer.

"The key finding in our work is that in the majority of cases, relapse is arising from a cell already present at the time of diagnosis," said James Downing, M.D., St. Jude Scientific Director, chair of the Department of Pathology and the paper's senior author. "That cell is selected for during treatment and then subsequently emerges as basis for relapse."

"The second key point is that we have found a large number of new genetic alterations that had not been previously identified as new targets of copy number changes at the time of relapse," Mullighan added.

Mullighan emphasized that the findings do not mean immediate treatments for ALL relapse. "But, this is a very important starting point because we have identified several key pathways that are the most common targets of new genetic changes at the time of relapse," he said.

Identification of these relapse pathways will lead to understanding of the biological machinery of relapse, and ultimately to drugs that target that machinery. Such studies of the relapse machinery are now underway at St. Jude.

In other further studies, the researchers are also looking for other relapse-related genetic alterations besides copy number abnormalities. They are also applying their findings to adult ALL, in which relapse is a more significant problem than in the childhood disease.

St. Jude Children's Research Hospital

---

---

	21st Century Pediatric Cancer Sourcebook: Childhood Acute Lymphoblastic Leukemia (ALL) - Clinical Treatment Data with Practical Information for Patients, Families, Physicians by Progressive Management Authoritative information and practical advice from the nation's cancer experts about childhood acute lymphoblastic leukemia (ALL), a form of pediatric cancer. Starting with the basics, and advancing to detailed patient-oriented and physician-quality information, this comprehensive compilation gives empowered patients, families, caregivers, nurses, and physicians the information they need to understand the diagnosis and treatment of this disease. Conveniently organized contents include: Incidence and Epidemiology * Risk Factors for Developing ALL * Overall Outcome for ALL * Cellular Classification and Prognostic Variables * Clinical and Laboratory Features at Diagnosis * Leukemic Cell Characteristics * Early Response to Treatment * Prognostic Groups * Prognostic groups under clinical...
	New Agents for the Treatment of Acute Lymphoblastic Leukemia by Vaskar Saha (Editor), Pamela Kearns (Editor) The majority of cancers present at a relatively advanced stage in which invasion within the primary organ is well established and metastases to lymph and distant organs are either clinically apparent or present at the microscopic level. However, it is increasingly recognized that the natural history of cancer formation is a long and complex path taking many years to develop to a clinically apparent stage in most cases. Furthermore, for most solid tumours there is a pre-invasive or intraepithelial stage of disease. This affords the opportunity for early detection and prevention of invasive disease and hence a cure. However, with this advancing knowledge comes a whole plethora of questions which will be explored in this monograph. Firstly, we need to understand the global burden of...
	Acute Lymphoblastic Leukemia: Etiology, Pathogenesis and Treatments (Cancer Etiology, Diagnosis and Treatments) by Severo Vecchione (Editor), Luigi Tedesco (Editor)
	The Official Patient's Sourcebook on Adult Acute Lymphoblastic Leukemia: A Revised and Updated Directory for the Internet Age by ICON Health Publications (Author) This book has been created for patients who have decided to make education and research an integral part of the treatment process. Although it also gives information useful to doctors, caregivers and other health professionals, it tells patients where and how to look for information covering virtually all topics related to adult acute lymphoblastic leukemia (also acute lymphoblastic leukemia; lymphoblastic leukemia; Lymphoid leukemia), from the essentials to the most advanced areas of research. The title of this book includes the word official. This reflects the fact that the sourcebook draws from public, academic, government, and peer-reviewed research. Selected readings from various agencies are reproduced to give you some of the latest official information available to date on adult...
	Recent Progress in the Treatment of Acute Lymphoblastic Leukemia, An Issue of Hematology/Oncology Clinics of North America, 1e (The Clinics: Internal Medicine) by Wendy Stock MD (Author), Meir Wetzler MD (Author) Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children, representing nearly one third of all pediatric cancers. The annual incidence of ALL is about 30 cases per million people, with a peak incidence in children aged 2-5 years. Although a few cases are associated with inherited genetic syndromes, the cause of ALL remains largely unknown. This issue presents articles that discuss current thinking on the diagnosis and treatment of the disease. Articles specifically emphasize molecular genetics, allogeneic stem cell transplantation, and treatments including, clofarabine, nelarabine, rituximab, and PegAsp.
	Chromosomes and Genes in Acute Lymphoblastic Leukemia (Medical Intelligence Unit) by Lorna M. Secker-Walker (Author) This monograph, written by one of the world's leading cytogeneticists in the field of hematology, decribes the large number of chromosome changes that have now been implicated in acute lymphoblastic leukemia (ALL). Both the well established method of banding and the newer fluorescence in-situ hybridisation, Southern blotting and polymerase chain reaction techniques are reviewed. A glossary of terms used in this field, essential for all non-chromosomal cogniscenti, is included. The most important translocations, partial deletions and chromosome gains and losses are illustrated and the clinical and molecular significance of each is described.
	What You Always Wanted To Know About Adult Acute Lymphoblastic Leukemia (Medical Basic Guides) by Jazzybee Publishing "What You Always Wanted To Know About..." are fully researched, straight-to-the-point, easily understandable and most comprehensive medical ebooks and guides for everybody. Whether you are just interested in the topic of the book or you are directly affected by it, these books can really help you with the information you need. All books including interactive tables-of-contents, this is your step toward new insights and informations. The contents of this book: General Information About Adult Acute Lymphoblastic Leukemia Stages of Adult Acute Lymphoblastic Leukemia Treatment Option Overview Chemotherapy Radiation therapy Chemotherapy with stem cell transplant Targeted therapy Biologic therapy Treatment...
	What You Always Wanted To Know About Childhood Acute Lymphoblastic Leukemia (Medical Basic Guides) by Jazzybee Publishing "What You Always Wanted To Know About..." are fully researched, straight-to-the-point, easily understandable and most comprehensive medical ebooks and guides for everybody. Whether you are just interested in the topic of the book or you are directly affected by it, these books can really help you with the information you need. All books including interactive tables-of-contents, this is your step toward new insights and informations. The contents of this book: General Information About Childhood Acute Lymphoblastic Leukemia Stages of Childhood Acute Lymphoblastic Leukemia Treatment Option Overview Chemotherapy Radiation therapy Chemotherapy with stem cell transplant High-dose chemotherapy Treatment Options for Childhood...
	21st Century Adult Cancer Sourcebook: Acute Lymphoblastic Leukemia (ALL) - Clinical Data for Patients, Families, and Physicians by Progressive Management Authoritative information and practical advice from the nation's cancer experts about adult Acute Lymphoblastic Leukemia (ALL) includes official medical data on signs, symptoms, treatment options, drugs, chemotherapy, staging, biology, prognosis, and survival, with a complete glossary of technical medical terms and current references. Starting with the basics, and advancing to detailed patient-oriented and physician-quality information, this comprehensive compilation gives empowered patients, families, caregivers, nurses, and physicians the knowledge they need to understand the diagnosis and treatment of ALL. A complete list of clinical trials related to ALL is included. ALL is an aggressive type of leukemia characterized by the presence of too many lymphoblasts or lymphocytes...
	Diagnostic dilemma.(acute lymphoblastic leukemia): An article from: Pediatric News by Dr. Stan Block (Author) This digital document is an article from Pediatric News, published by International Medical News Group on March 1, 2002. The length of the article is 498 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Diagnostic dilemma.(acute lymphoblastic leukemia) Author: Dr. Stan Block Publication: Pediatric News (Magazine/Journal) Date: March 1, 2002 Publisher: International Medical News Group Volume: 36 Issue: 3 Page: 2(2) Distributed by Thomson...