טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentItzkovich Chen
SubjectPlasma-sHLA Bound Peptides in Acute Myeloid Leukemia as
Predictors of Individual Response and their
Application in Immunotherapy
DepartmentDepartment of Medicine
Supervisor Dr. Yishai Ofran
Full Thesis textFull thesis text - English Version


Abstract

Acute myeloid leukemia is characterized by the accumulation of large numbers of abnormal cells that fail to differentiate into functional granulocytes or monocytes. Myeloid leukemia cell population is heterogeneous and composed of different immunophenotypical sub-populations. These leukemic sub-populations may also vary in their sensitivity to chemotherapy.

Over the last 30 years, AML treatment had not been changed and it includes an induction protocol with three consecutive days of Daunorubicin and seven consecutive days of Cytarabine. The same protocol applies regardless of gender, age, or genetic code. Recently it was recognized that as early as the first treatment, inherent chemo-resistant sub-populations are already exist, survive the chemotherapy, and may become dominant at relapse.

All vertebrates have a common immune mechanism, the major histocompatibility complex (MHC), which plays a pivotal role in the body’s defense mechanism. The MHC molecules are membrane bound molecules that possess a peptide-binding cleft. In humans, MHC is referred to as human leukocyte antigen (HLA). MHC is divided into two gene groups: MHC class I and class II.

HLA class I present peptides derived from intracellular degraded proteins. HLA molecules loaded with peptides to some extent are being released to the blood stream and even at normal conditioning can be detected in peripheral blood as soluble HLA.  

In cancer patients, numerous cancer-related peptides may be observed when elucidating the soluble HLA (sHLA) peptidome with biological assays. Patients with cancer have a much larger peptide repertoire compared to healthy donors. Furthermore, sHLA -bound peptides founded in the plasma of cancer patients were shown to be predominantly derived from disease cells. Therefore, cancer peptidome may be used to identify new targets for immunotherapy.

In this study, we analyzed sHLA peptides repertoire in BM plasma obtained from AML patients at different time points: at diagnosis, during chemotherapy induction, and in remission. Results are compared to the level of secreted sHLA bound peptides and peptides repertoire in normal healthy donors samples. Dynamic along different time points and quantitive assessment of disease specific peptides were studied as surrogate for clinical response, as well as to clarify the possible pathogenesis, resistance mechanism, and disease prognosis.

After rigorous selection process, three key peptides, WTS-1, GUCY1B3 AND SA-1, were selected as the most attractive candidates to serve as biomarkers. These peptides were highly observed among AML patients the protein it originate from is expressed in leukemic cells and may serve as immune targets.