טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentTurgeman Shira
SubjectThe Interaction Between Acute Myeloid Leukemia and
Microenvironment: The Role of Microenvironment in
Supporting Differential Proliferation
and Survival of Differentet...
DepartmentDepartment of Medicine
Supervisors Clinical Professor Tsila Zuckerman
Ms. Shlomit Yehodai-Reshef
Full Thesis textFull thesis text - English Version


Abstract

The interaction between Acute Myeloid Leukemia and microenvironment: The role of microenvironment in supporting differential proliferation and survival of different leukemia subclones

Acute myeloid leukemia (AML) is a hematological malignancy disease characterized with accumulation and expansion of dysfunction myeloid progenitor cells in the bone marrow (BM). Recent studies claim that AML is initiated by leukemic stem cell (LSC), a mutated hematopoietic stem cell (HSC), which proliferates and generates a malignant clone. Following chemotherapy, remission is achieved, however, the majority of patients will experience relapse. Relapse may be initiated by cells escaping chemotherapy stochastically or by cells unharmed by chemotherapy. Since the 5 years survival rate has not been change, better understanding of AML mechanism together with new treatment strategy is definitely required. The BM niche is composed of HSCs and the microenvironment cells, including Mesenchymal stromal cells (MSCs). This niche support HSCs production. In this study we hypothesized that in some AML patients, the disease is a result of MSCs dysfunction or impaired cross-talk between the MSCs and the AML blasts. The aims of this study were to characterize the AML-MSCs and to define the potential cross-talk with the AML blasts cells and to describe the contribution of the MSCs to leukemogenesis in active disease compare to complete remission state.

Based on our Patient’s own stroma (POS) system we established an AML POS bank of MSCs derived from different disease stages; Diagnosis, Remission, Relapse. We observed differences between AML-MSCs and Normal-MSCs including larger cell area, high heterogeneity in cells shape and slower growth rate of AML-MSCs compared to Normal-MSCs. In addition, we found that AML-cells grow better in a direct contact with POS. A specific cross-talk between POS and AML-cells was demonstrated by the ability of AML-cells to generate colonies, and by changes in CD34 expression. Moreover, cytokines and chemokines expression levels in the co-cultures of POS with AML-cells were higher for SDF1, SPP1, IL-6 and MCP-1, which are known as mediators in the interaction of POS and AML-cells co-cultures. Mutations in the microenvironment niche are known to be related to other cancers such as breast cancer, however mutations in AML MSCs are yet unknown. Screening for mutations in AML-MSCs raised point mutations in central genes as compared to Normal-MSCs. Those mutations may play a major role in MSCs and AML cells interaction and may contribute to leukemogenesis.

Importantly, the behavior of remission-MSCs, which is considered as healthy, has shown similar features to that of MSC from an active disease. These findings suggest that the remission-MSCs can provide an advantageous microenvironment to leukemogenesis and encourage the recurrence of the disease.


Overall, this study brings new insights on the contribution of MSCs to leukemogenesis. This work may pave the way to novel therapeutic strategies and better understanding of relapse mechanisms.