Exploring the Mechanisms of Resistance of Stem Cells Myeloproliferative Opposite of Tyrosine Kinase Inhibitors in 3d Model Niche Endosteal

Myeloproliferative disorders (MPD) include chronic myeloid leukemia (CML) (Ph +) and essential thrombocythemia (ET), the polycythemia vera (PV), myelofibrosis (MF) called SMP Ph. CML is the ultimate model of carcinogenesis. SMP is a characterized by a malignant monoclonal proliferation of a pluripotent hematopoietic progenitor determined by the presence of a balanced translocation between chromosomes 9 and 22 (Ph chromosome) which leads to major changes of a large number of cell functions. Investigators now believe that within the bone marrow exist two types of "hematopoietic niches' niche osteoblastic / endosteal and vascular niche, controlling the maintenance and differentiation of hematopoietic stem cell pool. The endosteal niche, is a hypoxic region near the endosteal trabecular, which provides protection to deeply dormant stem cells. Data from the literature suggest that in the SMP, especially CML, the interaction of malignant stem cells with the microenvironment niche Endosteal could favor their survival and resistance to treatment. The therapeutic management of CML was upset by the use of tyrosine kinase inhibitors (TKIs). However, despite these advances, even in situations of undetectable residual disease, it has been observed relapses of the disease stopped TKI leaving suggest that there is a resistance of leukemic stem cell to TKI.

Work in the group Bipoa "Bio Engineering and Pathophysiology Osteo-Articular" helped develop a 3D model of ex vivo bone formation, which can mimic the endosteal niche. the goal is to apply this model to the SMP of hematopoiesis by referring to normal hematopoiesis. it will be tested the hypothesis that the endosteal ex vivo recess of the 3D modeling allows to highlight a special interaction can promote the persistence of the leukemia stem cell despite the use of effective therapies.

Study Overview

• Status: Terminated
• Conditions: Myeloproliferative Disorders

• Study Type: Observational
• Enrollment (Actual): 200

Contacts and Locations

• Study Contact: Name: Laurence LEGROS, PH; Email: legros.l@chu-nice.fr
• Study Contact Backup: Name: Irit Touitou; Email: touitou.i@chu-nice.fr

Study Locations

• France
  • Nice, France, 06200
    • Chu de Nice

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The patients selected for this study, which will continue over a period of five years, corresponding to all newly diagnosed patients or SMP during TKI treatment in the clinical hematology department of Nice University Hospital and associated centers. The recruitment of three years should be 200 patients. Healthy donors are intra-family donor marrow taken to operating room under general anesthesia as part of their marrow donation. These healthy donors have also already signed a consent for their donation, including research referred to levies.

Description

Inclusion Criteria:

• Patients with LLC (chronic myeloid leukemia)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
patients
healthy volunteers; intrafamily marrow donors

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characteristics of cell CD34 + tumor from patients with SMP	Establishment of a stem cell CD34 + tumor bank from patients with SMP	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characteristics of the variation of TKI on CD4+ stem cells	Compare in vitro, in traditional culture or in a 3D environment mimicking endosteal niche, the effect of first and second generation TKIs on CD34 + stem cells made from patients with SMP or healthy volunteer donors	5 years

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nice
• Collaborators: Centre National de la Recherche Scientifique, France

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): April 1, 2020
• Study Completion (Actual): December 1, 2020

Study Registration Dates

• First Submitted: April 20, 2016
• First Submitted That Met QC Criteria: May 6, 2016
• First Posted (Estimated): May 9, 2016

Study Record Updates

• Last Update Posted (Actual): February 5, 2024
• Last Update Submitted That Met QC Criteria: February 2, 2024
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders
• Other Study ID Numbers: 14-PP-02