HLA Mutations, GvH Resistance and Relapse Following Allogeneic Hematopoietic Stem Cell Transplant
Jaroslaw Maciejewski
MD, PhDCleveland Clinic Foundation
Project Term: November 1, 2021 - October 31, 2024
This project investigates immunogenetic determinants of relapse following allogeneic stem cell transplant for myeloid neoplasia. Herein we will determine molecular modes of inactivation of HLA immunodominant peptide-presentation including HLA mutations, deletion and down modulation as a means of immunoescape. We will also study immunogenetic predictors of the strength of graft vs. leukemia according to the HLA divergence in the context of relapse, TCR repertoire diversity and HLA mutations.
Bone marrow transplantion remains the only curative option for patients affected by myeloid leukemias. A major limitation of the success of this procedure is the recurrence of leukemia. Therefore it is important to study the causes of the failure of the transplant to prevent leukemia from recurring. In addition to the chemotherapy administred during transplant to eliminate leukemia, it is believed that immune reactions mounted by the transplanted immune system of the donor are the most important factors allowing for eradiation of leukemic cells after transplant. However, the efficacy of such reaction is not absolute. In this proposal we will investigate the genetic causes of leukemia relapse related to “escape” of malignant cells from the control of the newly transplanted immune cells also referred to as “immune leukemia surveillance’ or “graft vs. leukemia” reaction. In the course of proposed studies we will uncover genetic factors of the donors which predict the strength of the anti-leukemic immune responses after transplant and how they relate to the ability of leukemia to evade these controls. Our preliminary data indicates that specific genetic changes occuring in leukemic cells enable them to be invisible to the graft vs. leukemia immune cells. The proposed investigations may improve prediction of propensity of the transplant to effectively control leukemia to establish diagnostic tools. We will also clarify the the actual mechanism of relapse to enable strategies that will be directed to prevent and to strengthen post-transplant immune control of leukemia.