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Monosomy 7- cancer that can start before we are born...

Childhood leukemia and myelodysplasia
$5,000 raised
of $5,000 goal
Fully funded!
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About the Researcher

Stella Davies, MBBS, PhD, MRCP
Cincinnati Children's Hospital


Read Stella's Story

Project Timeline:

Start:
In progress

Duration:
6 Months - 1 year

What your donation will fund:

  • $300 raised:
    buys tubes needed to test for monosomy 7 in different cell populations
  • $400 raised:
    buys plastic ware needed for the experiments
  • $500 raised:
    buys antibodies for flow cytometry
  • $800 raised:
    buys chemicals needed to separate cell populations for monosomy 7 testing
  • $1,000 raised:
    buys probes to test for monosomy 7 in different cells
  • $2,000 raised:
    buys supplies to grow the cells and test their ability to make leukemia cells

Project donors:

  • Anonymous
  • Lana Mak
  • Sarah Axness
  • elizabeth oakes
  • Reiko Osaki and Stephen Chan
  • Lori Gilinsky
  • Anonymous
  • Molly Lindquist
  • Michael Pellegrino
  • Anonymous
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  • Larissa Fontaine
  • Jessica Olifson
  • Michele Beuerlein
  • Dinah Meister
  • Mary Sims
  • Erin Hoffman
  • Shannon Growcock
  • Erica Goodridge
  • Rebekah Kennedy
  • Jamie Wilhelm
  • Jim Mulloy
  • Mark Haggard
  • Shelly Bierman
  • Paul Steele
  • Kasiani Myers
  • Elizabeth Roberts
  • Jennifer Hauser
  • Anonymous
  • Parinda Mehta
  • Teresa Smolarek
  • Stella Davies
  • Michael Grimley
  • Tracy Ashworth
  • Carol Del Prince
  • Anonymous
  • Rebecca Baird
  • Carrie Breitwieser
  • Carrie Gifford
  • Susan Laupola
  • Anne Witte
  • Daniel Leino
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Project abstract

Background.

When a child gets a cancer like leukemia, the first question parents ask is "Why?" Generally we have no answer for that question because we can’t look back in time and see what was happening before we knew the child was sick. Leukemia happening in a very young baby is unusual and especially hard to explain.  Recently we were given the gift of umbilical cord blood that had been stored by the parents of a 2 year old with a kind of blood cancer called monosomy 7. We were able to study the cord blood and show for the first time that the cancer had stated before the baby was born.
 
Project Description.
 
In this study, we will examine the rest of the stored cord blood and additional samples containing monosomy 7 to define the kind of blood cells that have become abnormal. We will also look at samples that we have collected serially to find out how other genetic changes contribute to make monosomy 7 into a cancer that is very hard to treat.
 
Objectives.
 
The objectives of this study are:
 
1. To identify the kind of blood cell that contains the genetic abnormality monosomy 7.
 
2. Test other genes in these cells to see if they are abnormal too.
 
Anticipated Outcomes.
 
We hope that what we learn in this study will help us find better treatments for children with monosomy 7. If the monosomy 7 occurs in a stem cell we will know that this can only be cured with bone marrow transplant. Abnormalities in other genes will allow us to pick the best kind of chemotherapy that will allow us to treat the children more effectively.
 

More scientific details about this project 

 
Origin and progression of Myelosdysplastic syndrome in patients with Bone Marrow Failure Disorders
  
 
Rationale: Inherited marrow failure disorders such as Fanconi anemia (FA), Shwachman Diamond Syndrome (SDS), Severe congenital neutropenia (SCN), Dyskeratosis congenita (DC) despite their different pathways of origin and genotypes, share a broad common phenotype consisting of progressive marrow failure and high risk of development of Myelosdysplastic syndrome (MDS), and acute myeloid leukemia (AML). Cumulative incidence of MDS/AML in FA is 22-33% by age 40 and around 30% in patients with DC (1-3). The general population has a lifetime risk for leukemia of less than 1%. Patients with marrow failure present an extraordinary opportunity to study the evolution of MDS and acute AML, due to their high risk and predictable progression over time. Children with underlying marrow failure disorders, offer a valuable resource for exploration of etiology, cell of origin and clonal expansion of cells carrying the clonal chromosomal abnormalities (the commonest being monosomy 7). Understanding disease mechanisms is key to the development of therapeutic strategies to improve currently poor outcomes for children with MDS/AML, especially in children with underlying marrow failure disorders.
 
Objectives: Our long-term goal is to understand and prevent development of monosomy 7 and other pre-leukemic clones in children with or without marrow failure disorder. The overall objective of this application, is to understand the cell-of-origin, and identification of co-operating genes, in children with monosomy 7, with and without an abnormal genetic background. In adults, monosomy 7 is believed to be one of a series of stochastically acquired genetic anomalies that accumulate likely over many years to complete the process of leukemogenesis.  Monosomy 7 arising in very young children likely has a different etiology and may contribute differently to leukemogenesis, as the young age of the children does not allow sufficient time for stochastic acquisition of mutation in the same way as older persons. Our central hypothesis is that unlike monosomy 7 associated with adult MDS, progression to MDS and emergence of AML in patients with underlying marrow failure disorders is a unique process starting very early in life and that patients with marrow failure can serve as a mechanistic model for de novo leukemogenesis and therapy-related leukemia in the general population. Our preliminary data indicate that clonal cytogenetic abnormalities (e.g. monosomy 7) monosomy 7 and other clonal abnormalities leading to MDS in children is a fetopathy originating in the hematopoietic stem cell (HSC) compartment, specifically present in the earliest hematopoietic precursors of the cord blood from one of our patients with FA and chromosome 1 abnormality and another patient without any marrow failure syndrome but with monosomy 7 MDS. Our multidisciplinary team is well prepared to undertake this project.  Our clinical programs, including a large pediatric oncology program, a comprehensive care clinic for children with FA following 150 children, and a comprehensive care clinic for children with marrow failure disorders following over 200 children ensure access to sufficient children for the aims proposed in this study. We have access to a number of patient samples, both with and without underlying marrow failure syndromes. 
 
Specific Aims. We will test our hypothesis with the following specific aims: 1A. Identify the cell of origin of the monosomy 7 and other clone/s in MDS arising in children with and without known marrow failure disorders (genetic predisposition), and establish timing of onset in very young children (in utero vs ex utero). Our working hypothesis is that the abnormal clone (monosomy 7 or others) will be present in the HSC compartment of children with MDS. Bone marrow, peripheral blood and cord blood (when available) samples will be analyzed using morphology, cytogenetics, cell sorting using flow-cytometry, compartmentalized FISH studies in sorted cells, microarray testing, and functional assessment using colony-forming units (CFUs). When available, these tests will be performed on serial samples to assess evolution of the clone and progression to leukemia. Further in depth investigation for cell-of-origin will include studying the karyotype of the mesenchymal stem cell compartment, using the clonal CFU-fibroblast (CFU-F) assay from these patient samples to determine whether the abnormal clone/s is confined to hematopoietic cells, or extends to more primitive mesenchymal-lineage fetal progenitors.
1B. Identify potential cooperating genes using the latest genomic platforms. We propose to sequence patients’ DNA to identify recurrent mutations in monosomy 7 or other common clonal abnormalities and also to identify other candidate genes that potentially cooperate in the pathogenesis of MDS/AML seen in patients with underlying marrow failure disorders - e.g. EZH2 and RABL5 (as shown in adults). These data will facilitate identification of potential novel targets for therapy.

Why is this important?

This project is designed to figure out what causes leukemia in children and how best to treat it. When we understand better when the leukemia starts, and in which kind of cell, we can start to address what the cause is, and figure out how to prevent leukemia. Moreover, knowing more about what is going on inside the leukemia cells will help us pick the best treatments for these children. Older people also get leukemia that has the genetic abnormality monosomy 7, so this information will benefit them as well.

Who will benefit from the results of this project?

This project will mainly benefit children, but it might benefit older patients too.

Stella Davies, MBBS, PhD, MRCP

I have been a pediatric oncologist for over 30 years and I have had to tell a lot of parents that their beloved child has cancer. Every parent asks the question "why my child", and every parent asks "what did I do wrong" - as parents we all feel guilty when something bad happens to our child. I have never had a good answer for these questions, and although I reassure parents that they did nothing wrong, I want to answer that key question of why and when did it happen. For over 30 years I have looked after hundreds of children with cancer and I have seen survival rates improve markedly, but still we cannot cure all the children. I remember the children who are cured with joy and pride, but I carry in my heart the children who are lost. We honor the children who are lost with research, so that we can do better for the children who come after them -- and that work is not complete until all of these children can be cured.

Education & Training

Year Institution Degree Field
1993 University of Minnesota, Minneapolis Clinical and Research Fellow Pediatric Hematology/Oncology & Bone Marrow Transplantation
1989 Royal Victoria Infirmary, Newcastle-Upon-Tyne, England On Call Registrar Pediatric Intensive Care
1989 Newcastle General Hospital, Newcastle-Upon-Tyne, England Registrar Pediatrics/Pediatric Neurology and Neuro-Oncology
1989 University of Newcastle-Upon-Tyne, England PhD Molecular Biology; Mentor: Professor Adrian L. Harris, Department of Clinical Oncology
1985 Newcastle General Hospital, Newcastle-Upon-Tyne, England Senior House Officer and Registrar Pediatrics, Neonatal Pediatrics and Pediatric Hematology/Oncology
1985 Great Ormond St. Hospital, London, England Senior House Officer Pediatrics and Pediatric Hematology/Oncology
1983 Royal Victoria Infirmary, Newcastle-Upon-Tyne, England Senior House Officer/Registrar Internal Medicine, Hematology and Bone Marrow Transplantation
1981 University of Newcastle-Upon-Tyne Medical School MBBS Bachelor of Medicine, Bachelor of Surgery, with First Class Honors

Awards & Leadership

Year Award/Position
Jacob G. Schmidlapp Endowed Chair and Professor of Pediatrics; Cincinnati Children's Hospital Medical Center
Co-Director, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center
Director, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center
Editorial Board Member “Journal of Clinical Oncology” 2006- 2010
Editorial Board Member “Blood” 2003-current
Editorial Board Member and feature contributor “Pediatric Blood and Cancer” 2003-current
Editorial Board Member “Pediatric Hematology and Oncology” 2002- 2006
Special Features Editor and Editorial Board Member “Medical and Pediatric Oncology” 2001-2004
ASH Communications Committee Member, 2007- current
NIH review panel: PAR-00-25, 2002
NIH review panel: PAR-021-10-01, 2001
Co-Chair, Pediatric Cancer Committee, Center for International Bone Marrow Transplant Research, 2004-2011
Member, Alex’s Lemonade Stand Grant Review Committee, 2009-current
2011 Children’s Oncology Group Scientific Council
2010 Board Chair, MACC Fund Scientific Advisory Board
1997 Children’s Cancer Group Clinical Science Junior Faculty Award
1996 McQuarrie Research Award, University of Minnesota
1995 American Society of Clinical Oncology Career Development Award
1993 American Society of Hematology Travel Award
1993 American Society of Pediatric Hematology and Oncology Young Investigator Award
1992 American Society of Hematology Travel Award
1981 Goyder Scholarship for Clinical Medicine and Surgery
1981 Undergraduate Special Research Study Prize
1981 Dickinson Prize for Surgery
1981 Phillipson Prize for Best Graduate, University of Newcastle-Upon Tyne
1981 McNaughton Prize for Best Female Graduate, University of Newcastle Upon-Tyne
1980 Mary Gordon Bursary Award

Seed Growing into Tree

Nov 19, 2014

We used our Consano money to get preliminary data that has allowed us to get a grant of $100,000 to work on this project, and now have an invitation from a private foundation to apply for an even bigger grant- our Consano seed is growing into a big tree! Thank you all for your generous support!

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