Neoplasms

Immune System Diseases

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Mastocytosis

Anaphylaxis

Mast Cell Activation Disorders

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Observational study of all patients referred for suspected mast cell disease. Collection of blood or bone marrow for analysis during diagnostic procedures.

5-8 cc blood or bone marrow was additionally collected for analysis during diagnostic procedures. No assigned interventions.

Collection of blood and bone marrow

Cem Akin, M.D., Ph.D.

Mastocytosis is a disorder characterized by presence of excessive numbers of mast cells in skin, bone marrow and internal organs. It can affect both children and adults, males and females and individuals from all ethnic backgrounds, although precise demographic information about the affected populations is not available as it is a rare disorder. Mastocytosis in children is generally limited to the skin and follows a self limited course, while it is a disorder of the hematopoietic stem cell associated with somatic mutations of the c-kit gene in most patients with adult-onset of disease. There is no known curative therapy for most patients with systemic mastocytosis. Recent research studies identified several subtypes of disease with distinct clinical and pathologic features, however, a precise understanding of the incidence as well as molecular pathology of different disease subtypes is lacking. This study aims to examine molecular and cellular pathological aspects of disease in patients with mastocytosis and correlate findings with clinical presentation and prognosis. Patients will undergo a routine history and physical examination, and diagnostic tests will be ordered as dictated by each patient's clinical presentation. Blood and bone marrow will be obtained for diagnostic and research purposes. Genetic analysis of the c-kit gene regulating mast cell growth and differentiation will be performed. It is hoped that findings obtained from this study will help to design novel therapies for mastocytosis and other disorders in which mast cells play a critical role.

Molecular Mechanisms and Diagnosis of Mastocytosis

Investigation of Cellular and Molecular Pathologic Mechanisms in Mast Cell Disorders.

Patients were categorized into one of the clonal and non-clonal mast cell disorder categories after availability of diagnostic data

KIT D816V mutation was assessed in patient samples containing various proportions of neoplastic mast cells.

University of Michigan

Assistant Professor

Blood and Lymph Conditions

Symptoms and General Pathology

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Hematologic Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Myeloid Leukemia

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Amino Acids

Tyrosine Kinase Inhibitors

Tyrosine

Patients newly diagnosed for Chronic Myeloid Leukemia, according to inclusion and exclusion criteria

Collection of blood and bone marrow in order to identify epigenetic abnormalities and their consequences in surviving CML cells after 3 months of TKI treatment

Patrick LACARIN

Anne PARRY, MD

Gabriel ETIENNE, MD

Atchroue JOHNSON ANSAH, MD

Marc BERGER

Stéphane COURBY, MD

Valérie COITEUX, MD

Franck-Emmanuel NICOLINI, MD

Marie BALSAT, MD

Gabrielle ROTH-GUEPIN, MD

Jean Michel KARSENTI, MD

Ali TURHAN, MD

Lydia ROY, MD

Laurence LEGROS, MD

Delphine REA, MD

Emmanuelle TAVERNIER, MD

Philippe ROUSSELOT, MD

Primary objective : To identify epigenetic dysregulations of in vivo TKI-resisting CML cells Hypothesis : An epigenetic dysregulation is involved in the in vivo survival of a CML cell subclone despite the use of TKIs

Chronic myeloid leukemia (CML) is a model of leukemogenesis because the malignant transformation of a hematopoietic stem cell is considered as the consequence of a unique major event: the translocation t(9;22) which is able to produce the BCR-ABL chimeric protein. The treatment of CML has made considerable progress with the development of tyrosine kinase inhibitors (TKI) targeting the BCR-ABL protein activity. Despite the efficacy of these drugs, several studies showed the existence of intra-clonal heterogeneity and the in vivo survival of a leukemic stem cell (LSC) subset by:

* A detectable residual disease in the majority of cases, and after treatment for several years.
* The relapse of about half of patients after stopping TKI; these relapses are the proof of the in vivo persistence of LSC, even when CML clone is particularly sensitive to TKI.
* Cases of unexplained TKI resistance (no BCR-ABL mutation etc...)

The mechanisms involved in in vivo survival of LSC remain largely unknown. Mechanisms independent of BCR-ABL TK activity could be responsible of LSC survival. However, the fact that CML is the consequence of t(9; 22) if it appears in a HSC, suggests that a stem cell specific biological status should play a role in the emergence of the disease and probably the special feature of this cell subset. Several studies showed the essential role of epigenetic factors in stem cell behavior (quiescence, self-renewal, or differentiation process). Epigenetic dysregulation of some gene expression was observed in CML cells and changes in DNA methylation are involved in CML progression towards accelerated or blast phase, more resistant to TKIs. These observations led to clinical trial combining TKI with epigenetic drugs which results confirmed the in vivo involvement of epigenetic mechanisms during CML progression. However, the role of epigenetics in the early resistance of a chronic phase CML cell subset remains unknown.

The hypothesis is that epigenetic features could participate in TKI resistance of CML LSC and their survival in bone marrow.

In order to identify new mechanisms and/or new targets involved in LSC resistance, investigator choose a global approach of DNA methylation profile with an HM450K microarray. Investigator analyzed the sorted CML CD34+ CD15- cell subset (n=6) in comparison with: 1) CD34+ CD15- cells from healthy donors (hematopoietic grafts), in order to eliminate specificities of normal hematopoietic hierarchy, 2) the CD34-CD15+ sub-clone from the CML clone before any treatment in order to eliminate characteristic of CML mature compartment. The CD34+CD15- cells showed a specific DNA methylation profile, from diagnosis and from this level of cell hierarchy ((Bourgne et al., oral communication, SFH meeting 2017, manuscript submitted). In order to identify biomarkers specific to CML cells, investigator removed abnormally methylated regions that are differently methylated during hematopoietic differentiation. After this step, 825, 2210 and 1461 probes identified regions specifically dysmethylated in CD34-CD15+, CD34+ CD15- CML cells and both respectively. Investigator also observed changes in expression of epigenetic actors. These results validate our hypothesis. With the recent data published in literature, they strongly argue in favor of the involvement of epigenetic dysregulation in native intra-clonal heterogeneity, and justify this original translational research project.

EPIgenetics and in Vivo Resistance of Chronic Myeloid Leukemia Stem Cells to Tyrosine Kinase Inhibitors

Collection of Biological Resources During Medical Care of Patients With Chronic Myeloid Leukemia (CML) in Chronic Phase for an Epigenetic Study of Leukemic Stem Cells

Epigenetic and/or gene expression anomalies in in vivo TKI-selected CML cells for 3 months in comparison with anomalies identified at D0

To identify in primary CML clones the shared epigenetic marks and/or deregulated genes of 3 months TKI-resistant cells and their relationship with CML burden at M3

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Molecular Mechanisms and Diagnosis of Mastocytosis	NCT00336076	Mastocytosis	Collection of b...	-	University of Michigan
EPIgenetics and in Vivo Resistance of Chronic Myeloid Leukemia Stem Cells to Tyrosine Kinase Inhibitors	NCT03481868	Chronic Myeloid... Chronic Phase	Collection of b...	18 Years -	University Hospital, Clermont-Ferrand

Spots Global Cancer Trial Database for collection of blood and bone marrow