Protocol Number: 09-I-0086



Title: Screening Protocol for Genetic Diseases of Mast Cell Homeostasis and Activation
Number: 09-I-0086
Summary: Background:

- Mast cells are responsible for most symptoms of allergic reactions. In some allergic diseases, it is unusually easy to cause mast cells to release their contents and cause allergic reactions. In other cases, mast cells grow abnormally and, in rare cases, can result in tumors. Mast cells also control other parts of the immune system.

- Understanding why mast cells behave abnormally in allergic diseases is important to finding better ways for diagnosing and treating these potentially life-threatening disorders.

Objectives:

- To screen mast cells at the genetic and functional levels to characterize abnormalities, identify mutations, detect carrier states, and/or develop therapies for such disorders.

- To create a library of information about inherited diseases of mast cell homeostasis and activation, including piebaldism (problems with skin and hair pigmentation), anaphylaxis (severe allergic reaction), allergies, asthma, atopic dermatitis (eczema), allergic rhinitis ( hay fever ), food allergies, urticaria/angioedema (hives/swelling), immunodeficiency diseases, and autoimmune diseases.

Eligibility:

- Patients between the ages of 1 and 80 years who have been referred by a physician and are known to have or be suspected of having an inherited disorder of mast cells, in particular patients (and their relatives) with piebaldism, allergies, or anaphylaxis that is not caused by allergies.

Design:

- Study population will consist of up to 250 participants in a 5-year period. One third of the study population will consist of patients; the other two thirds will consist of biological relatives.

- Evaluation is limited to testing on blood specimens; no treatment will be provided.

- Clinical and research laboratory evaluations of patients will include the following:

- Clinical evaluation and previous laboratory tests as documented in outside medical records by health care providers. A standard questionnaire will also be administered at the time of subject enrollment.

- Blood collection for clinical laboratory testing, tailored to each subject's clinical evaluation where appropriate (5 ml).

- Blood collection for research laboratory testing, tailored to each subject's clinical evaluation-including genetic screening and assessment of mast cell growth and functioning-and storage of additional frozen blood specimens for future studies (up to an additional 30 ml).

- Evaluations of blood relatives will include the following:

- Clinical evaluation as documented from outside medical records by health care providers and administration of a standard questionnaire.

- Blood collection where indicated for diagnostic or research purposes.

- After 12 consecutive months on the study, results from initial evaluation will be reviewed. Subjects with findings deemed to be of continued interest will be contacted and invited to remain as active participants to this protocol for another year, provided that they renew their consent to participate.


Sponsoring Institute:
National Institute of Allergy and Infectious Diseases (NIAID)
Recruitment Detail
Type: Participants currently recruited/enrolled
Gender: Male & Female
Referral Letter Required: Yes
Population Exclusion(s): None

Eligibility Criteria:
INCLUSION CRITERIA:

- Subjects, ages birth to 80 years old, known to have or suspected of having an inherited disorder of mast cell homeostasis or activation, in particular patients with piebaldism or idiopathic anaphylaxis, will be eligible for enrollment. In the latter case, because of the intensive time and labor required for research laboratory testing, subjects will be enrolled only if in the opinion of the investigator (based on discussions with the patient's private physician) there is a high index of suspicion of a mast cell disorder. Blood relatives of enrolled subjects will be eligible for enrollment. There will be no discrimination as to age, gender, race, or disability.


- Subjects must have a health care provider outside of the NIH.


- Subjects/guardians must be willing and able to give informed consent.


- Subjects must agree to have their blood stored for future studies of the immune system and/or other medical conditions.


- Women will be included in the study, including those who are lactating or may be pregnant.


- Children will be included in the study.


EXCLUSION CRITERIA:


- The presence of an acquired abnormality of the immune system, such as cytotoxic chemotherapy or malignancy, may be grounds for possible exclusion if, in the opinion of the investigator, the presence of such a disease process would interfere with evaluation.


- Subjects with a history of HIV or evidence of chronic Hepatitis B and/or C infection will be excluded.


Special Instructions:
Currently Not Provided
Keywords:
Mast Cells
Piebaldism
Anaphylaxis
Allergy
Genetics
Recruitment Keyword(s):
Anaphylaxis
Allergy
Mast Cells
Condition(s):
Piebaldism
Idiopathic Anaphylaxis
Allergy
Chronic Urticara
Angioedema
Investigational Drug(s):
None
Investigational Device(s):
None
Intervention(s):
None
Supporting Site:
National Institute of Allergy and Infectious Diseases

Contact(s):
Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):
Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, Metcalfe DD. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10560-4.

Worobec AS, Semere T, Nagata H, Metcalfe DD. Clinical correlates of the presence of the Asp816Val c-kit mutation in the peripheral blood mononuclear cells of patients with astocytosis. Cancer. 1998 Nov 15;83(10):2120-9.

Kirshenbaum AS, Goff JP, Semere T, Foster B, Scott LM, Metcalfe DD. Demonstration that human mast cells arise from a progenitor cell population that is CD34(+), c-kit(+), and expresses aminopeptidase N (CD13). Blood. 1999 Oct 1;94(7):2333-42.


Clinical Trials Number:
NCT00852943



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Oh yeah...

I meant to respond to that one.  Autoimmune disorders run in my family.  Both of my kids had eczema and my son is allergic to peanuts.  (He was also allergic to corn, but thankfully he grew out of that!).  And then I have this mast cell disorder... we should be a good family to study

Thanks for the reminder,
Heather

KIT-D816V-independent oncogenic signaling in neoplastic cells in systemic mastocytosis: role of Lyn and Btk-activation and disruption by dasatinib and bosutinib.
Gleixner KV, Mayerhofer M, Cerny-Reiterer S, Hörmann G, Rix U, Bennett KL, Hadzijusufovic E, Meyer RA, Pickl WF, Gotlib J, Horny HP, Reiter A, Mitterbauer-Hohendanner G, Superti-Furga G, Valent P.
SourceDepartment of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria;

Abstract
Systemic mastocytosis (SM) either presents as a malignant neoplasm with short survival or as an indolent disease with normal life-expectancy. In both instances, neoplastic mast cells (MC) harbor D816V-mutated KIT, suggesting that additional oncogenic mechanisms are involved in malignant transformation. We here describe that Lyn and Btk are phosphorylated in a KIT-independent manner in neoplastic MC in advanced SM and in the MC leukemia line HMC-1. Lyn- and Btk activation was not only detected in KIT D816V-positive HMC-1.2 cells, but also in the KIT D816V-negative HMC-1.1 subclone. Moreover, KIT D816V did not induce Lyn/Btk-activation in Ba/F3 cells, and deactivation of KIT D816V by midostaurin did not alter Lyn/Btk activation. siRNAs against Btk and Lyn were found to block survival in neoplastic MC and to cooperate with midostaurin in producing growth inhibition. Growth inhibitory effects were also obtained with two targeted drugs, dasatinib which binds to and blocks KIT-, Lyn-, and Btk-activation in MC, and bosutinib, a drug that deactivates Lyn and Btk without blocking KIT activity. Together, KIT-independent signalling via Lyn/Btk contributes to growth of neoplastic MC in advanced SM. Dasatinib and bosutinib disrupt Lyn/Btk-driven oncogenic signalling in neoplastic MC, which may have clinical implications and explain synergistic drug interactions.

PTEN-deficiency in mast cells causes a mastocytosis-like proliferative
Abstract
Kit regulation of mast cell proliferation and differentiation has been intimately linked to the activation of phosphatidylinositol 3-OH kinase (PI3K). The activating D816V mutation of Kit, seen in the majority of mastocytosis patients, causes a robust activation of PI3K signals. However, whether increased PI3K signaling in mast cells is a key element for their in vivo hyperplasia remains unknown. Here we report that dysregulation of PI3K signaling in mice by deletion of the phosphatase and tensin homolog (Pten) gene (which regulates the levels of the PI3K product, phosphatidylinositol 3, 4, 5-trisphosphate) caused mast cell hyperplasia and increased numbers in various organs. Selective deletion of Pten in the mast cell compartment revealed that the hyperplasia was intrinsic to the mast cell. Enhanced STAT5 phosphorylation and increased expression of survival factors, like Bcl-XL, were observed in PTEN-deficient mast cells and these were further enhanced by stem cell factor stimulation. Mice carrying PTEN-deficient mast cells also showed increased hypersensitivity as well as increased vascular permeability. Thus, Pten deletion in the mast cell compartment results in a mast cell proliferative phenotype in mice, demonstrating that dysregulation of PI3K signals is vital to the observed mast cell hyperplasia.

Submitted September 28, 2010.
Accepted September 6, 2011.
Copyright © 2005 American Society of Hematology