טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentKenigswald Ella
SubjectThe Role Myeloid Derived Suppressor Cells (MDSC) in
Supporting Acute Myeloid Leukemia (AML)
Proliferation
DepartmentDepartment of Medicine
Supervisors Dr. Yishai Ofran
Dr. Igal Louria-Hayon
Full Thesis textFull thesis text - English Version


Abstract

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitors. Secondary AML (s-AML) is characterized by a previous disease diagnosis of MDS or MPN.

Myeloid derived suppressor cells (MDSCs) are myeloid cells which play a critical role in tumor associated immune suppression and may also support tumor growth. Their function in the context of AML development is still unknown. MDSCs are subdivided into monocytic-MDSCs and granulocytic-MDSCs. Here, we asked whether MDSCs educated within a solid tumor environment can support AML. MDSCs were examined from different aspects. Firstly, human MDSCs derived from peripheral blood of patients who underwent surgical resection of malignant and benign solid tumors were examined. MDSCs were also studied in a mouse model.

We examined solid tumor derived MDSCs’ ability to migrate to hematopoietic organs as well as MDSCs’ proliferative and anti-apoptotic effect on AMLFor this purpose, cancer cells (LLC cell line) were injected into mice and 16 days later, spleen MDSCs were isolated .These MDSCs were injected intravenously  into recipient mice in order to examine the infiltration of the injected MDSCs’ and their to the BM, blood, and spleen, which was assessed by FACS. Next, AML proliferation and apoptosis assays were conducted and the ability of MDSCs to support patient-derived leukemia cell lines and AML blasts was examined. Supernatants were collected from samples of the above ex-vivo experiments and examined in order to further understand the communication between the AML and the MDSCs. ELISA was performed to detect cytokines secreted by MDSC that might affect AML. The supernatants (without the presence on the MDSCs) derived from MDSCs were tested for their ability to support AML proliferation. These assays were done; to test whether the communication between AML and the MDSCs involves physical cell contact dependent communication, cytokine secretion, or a combination of both.

The results of these experiments showed that MDSCs have the ability to migrate from peripheral blood to the bone marrow. AML blast cells showed increased proliferation when cultured together with MDSCs as well as improved survival (as examined by apoptosis assay). In the human MDSC experiments, the granulocytic- MDSC number increased towards the end of the surgery and 48 hours later in both malignant and non-malignant patients, while monocytic-MDSC levels show an increase toward the end point of the surgery followed by a drastic decrease at the 48 post-operation time point in the malignant patients. The results suggest that MDSCs are able to affect and support AML proliferation and viability and are also can migrate to the BM, where AML are originated. Therefore, MDSCs may be considered as amajor pro-cancerous factor in AML development.