Progress Regarding Hypodiploid Acute Lymphoblastic Leukemia – “HALL”
In conjunction with Dr. Steven Hunger (Colorado Children’s Hospital and Chair of the ALL (Acute Lymphoblastic Leukemia) Committee of the Children’s Oncology Group*) and Dr. Charles Mullighan (St. Jude’s Research Hospital) and other members of the National Children’s Oncology Group, The Henry Schueler 41 & 9 Foundation helped sponsor the most comprehensive analysis of Hypodiploid ALL (“HALL”) ever performed. This type of ALL that Henry was afflicted with is extremely rare. In fact, only 124 samples of “HALL” are known to exist in the United States. Yet ALL is the most common form of pediatric leukemia and despite improvements in the outcome of therapy for ALL, this disease remains the most common cause of cancer-related death in young people.
Hypodiploid ALL or “HALL”, with fewer than 44 chromosomes is characterized by multiple whole-chromosomal losses and extremely poor outcomes. This project led to a gene analysis of samples from patients with three different forms of this rare leukemia to confirm genetic differences that could lead to new treatments.
Research led by St. Jude Children’s Research Hospital scientists has identified a possible lead in treatment of two childhood leukemia subtypes known for their dramatic loss of chromosomes and poor treatment outcomes.
The findings also provide the first evidence of the genetic basis for this high-risk leukemia. Normal human cells have 46 chromosomes, half from each parent, but hypodiploid ALL is characterized by fewer than 44 chromosomes. Chromosomes are highly condensed pieces of DNA, the molecule that carries the inherited instructions for assembling and sustaining a person. The research appeared in the January 20, 2013 advance online edition of the scientific journal Nature Genetics.
The study, the largest ever focused on hypodiploid ALL, confirmed that this tumor has distinct subtypes distinguished by the number of chromosomes lost and the submicroscopic genetic alterations they harbor. Researchers found evidence suggesting more than one-third of patients with a subtype known as low hypodiploid ALL have Li-Fraumeni syndrome. Families with Li-Fraumeni syndrome harbor inherited mutations in the TP53 tumor suppressor gene and have a high risk of a range of cancers. Hypodiploid ALL had not previously been recognized as a common manifestation of Li-Fraumeni syndrome.
Significantly, researchers reported that the major hypodiploid subtypes are both sensitive to a family of compounds that block the proliferation of cancer cells. The compounds include drugs already used to treat other cancers. The subtypes are low hypodiploid ALL, characterized by 32 to 39 chromosomes, and near haploid ALL, which has 24 to 31 chromosomes.
“This study is a good example of the important insights that can be gained by studying the largest possible number of patients in as much detail as possible. This approach led us to key insights about these leukemia subtypes that we would otherwise have missed,” said the study’s senior and corresponding author, Charles Mullighan, MBBS(Hons), MSc, M.D., an associate member of the St. Jude Pathology Department. Mullighan is a Pew Scholar in Biomedical Sciences.
The near haploid and low hypodiploid ALL subtypes represent 1 to 2 percent of the estimated 3,000 pediatric ALL cases diagnosed annually in the U.S. But they account for a much larger number of ALL treatment failures. Today more than 90 percent of young ALL patients will become long-term survivors, compared to 40 percent for patients with these two high-risk subtypes. St. Jude researchers led the study in collaboration with investigators from the Children’s Oncology Group, the world’s largest organization devoted exclusively to childhood and adolescent cancer research.
Note the authors’ recognition of Hank’s living wish below:
“The cure rate for hypodiploid ALL is only about half that obtained overall for children with ALL. The findings of this study are very important and have the potential to impact how this high-risk subset of childhood ALL is treated,” said Stephen Hunger, M.D., chair of the Children’s Oncology Group ALL committee and one of the paper’s co-authors. “This study grew out of the efforts of Hank Schueler, a teenager who died from hypodiploid ALL. He wanted to find ways to help treat other children with this type of leukemia. After he passed away, his parents established a foundation to support research in hypodiploid ALL. We thought that one way to do this was to conduct the genomic analyses reported in this paper. These findings would not have been possible without Hank’s idea and without support from the Schueler family.”
And note the importance that is given to this discovery for other children:
“Identification of children with low-hypodiploid ALL and inherited TP53 mutations could help expand the use of life-saving cancer screening,” said Linda Holmfeldt, Ph.D., a St. Jude postdoctoral fellow. She and Lei Wei, Ph.D., of the St. Jude Department of Computational Biology and formerly of Pathology, are the study’s co-first authors. “Screening helps save lives by finding cancers much earlier when the odds of a cure are greatest,” Holmfeldt said.
And these findings and the potential screening benefits for other children would not have been possible with the generous love and support from all of you that are reading this newsletter. Thanks for your support.
We are continuing to support this study at St. Jude’s. The Foundation has agreed to fund a two-year clinical research technician position (the “Henry Schueler 41 & 9 Senior Research Technologist”) at St. Jude’s where they will assist senior researchers Dr. Mullighan and Linda Holmfeldt, Ph.D. as they conduct future studies that will provide new insights into the induction and development of leukemia and identify new therapeutic strategies for Hypodiploid ALL. St. Jude’s has hired Roberta Marino to their team studying “HALL”. A short bio follows. We welcome Roberta to this important position and the 41 & 9 family!
Roberta Marino: A native of Brazil, Roberta obtained her B.S. in 2001 in Biological Sciences at Mackenzie Presbyterian University, São Paulo. She graduated with a Master of Science degree in 2004 from the Federal University of São Paulo with work focusing on mesenchymal stem cell (MSC) therapy geared towards cures for neurodegenerative diseases, particularly Amyotrophic Lateral Sclerosis (Lou-Gehrig-Disease). Roberta obtained her Ph.D. in Biomedical Sciences in a joint program administered by the Federal University of São Paulo, Brazil, the University of Tennessee and St. Jude Children’s Research Hospital in Memphis, Tennessee. Roberta’s thesis was focused on bone marrow osteoprogenitors and their niche. She developed her first post-doctoral fellowship at The Children’s Hospital of Philadelphia where she joined the Department of Oncology to work with multipotent mesenchymal stromal cells as a vehicle for anti-tumor drugs. Her second post-doctoral fellowship was also at CHOP where she joined the Department of Neonatology and her main project was to evaluate the influence of certain growth factors on stress hematopoiesis. In October of 2011 she accepted a position as a research associate at the University of Wisconsin-Madison. Her research was focused on the evaluation of a novel phospholipid-ether compound in pediatric (e.g. neuroblastoma) and adult cancer (e.g. multiple myeloma). The compound can be used for simultaneous tumor imaging and cancer therapy.
*Footnote: The Children’s Oncology Group: The Children’s Oncology Group (www.childrensoncologygroup.org) is the world’s largest organization devoted exclusively to childhood and adolescent cancer research. The Children’s Oncology Group (COG) unites more than 8,000 experts in childhood cancer at more than 200 leading children’s hospitals, universities, and cancer centers across North America, Australia, New Zealand, and parts of Europe in the fight against childhood cancer. Today, more than 90 percent of the 13,500 children and adolescents diagnosed with cancer each year in the United States are cared for at COG member institutions. Research performed by the Children’s Oncology Group institutions over the past fifty years has transformed childhood cancer from a virtually incurable disease to one with a combined 5-year survival rate of 80 percent. COG’s mission is to improve the cure rate and outcome for all children with cancer.
Progress Regarding Zygomycosis (Mucormycosis)
Zygomycosis, also known as mucormycosis, is a disease that attacks cancer patients like Hank and others when their host defenses are compromised by treatment. Though Hank’s leukemia had resurfaced following his bone marrow transplant in September, 2007 it was this deadly fungal infection which eventually robbed him of his eyesight and ultimately took his life in December of 2007. Through your generosity the Foundation was able to publish in 2012 (Oxford University Press) a medical and scientific supplement on Zygomycosis which reached almost 12,000 medical subscribers worldwide. Our Foundation sponsored the conference which generated this research and then paid for its subsequent publication after its acceptance by the prestigious journal, Clinical Infectious Disease (“CID”). It is entitled “Advances Against Mucormycosis: A Tribute to the Memory and Courage of Hank Schueler”.
This Supplement was edited by Dr. Thomas Walsh, the Director of the new Transplantation-Oncology Infectious Diseases Program at Cornell University Medical Center (Weill-Cornell Medical College and New York Presbyterian Hospital) in New York. It is widely held as the most comprehensive and authoritative body of research on the subject of mucormycosis in the world.
Shortly after its publication, Dr. Walsh wrote a note to the Study’s authors and members of the Henry Schueler Foundation Board:
Dear Co-authors and Members of the Board of the Henry Schueler 41& 9 Foundation,
Enclosed is the complete publication of our work, “Advances Against Mucormycosis: A Tribute to the Memory and Courage of Hank Schueler.” This CID Supplement is available in the public domain through your expertise and generosity to serve as a powerful resource to guide the management and research of mucormycosis. I thank you for your dedication, knowledge and compassion in honoring the memory of Hank and in securing a better future for our patients who will battle this terrible infection.
In 2013, Dr. Walsh was also named as the Henry Schueler 41 & 9 Foundation Scholar. This title accompanies all of his correspondence, manuscripts, and other publications and confers greater public awareness of the Henry Schueler 41 & 9 Foundation and assists Dr. Walsh in pursuing the Foundation’s mission in mucormycosis. His Mission and ours is to develop new strategies for diagnosis, treatment, and prevention of invasive mucormycosis., increase public awareness of the epidemiology, morbidity and mortality of invasive mucormycosis., and to provide expert outreach assistance to patients with mucormycosis, their families, and their physicians.
In May of 2013, Dr. Walsh gave the Inaugural Henry Schueler 41 & 9 Foundation Scholar Lecture on Mucormycosis at Northwestern. The event was chaired by Dr. John Flaherty, a Sauganash resident, who serves as Professor of Medicine and Associate Chief, Division of Infectious Diseases at Northwestern University Feinberg School of Medicine.
The turnout was excellent and discussion afterward was enthusiastic. The Lecture served as an important benchmark for our past achievements and future plans.
Advances Against Mucormycosis: A Tribute to the Memory and Courage of Hank Schueler
Clinical Infectious Diseases: Volume 54 suppl 1 February 1, 2012