Adoptive Immunotherapy for Chronic Myeloid Leukemia in a Mouse Model.
myeloid leukemia (CML) is a myeloproliferative neoplasm caused by t(9;22) chromosomal
translocation that creates the Philadelphia chromosome. The translocation encodes a
constitutively active tyrosine kinase, BCR-ABL1, which turns a normal hematopoietic stem
cell into a leukemic stem cell (LSC). BCR-ABL1 does not affect lineage differentiation.
Therefore, CML is characterize... read mored clinically by the overproduction of maturing cells of
the neutrophil lineage. Although tyrosine kinase inhibitors (TKIs) are the current
preferred initial treatment for CML, eradication of the disease is rarely achieved. Low
levels of BCR-ABL1 transcripts, thought to originate from primitive leukemia stem cells,
persist in most TKI-treated patients and lead to disease relapse after TKI withdrawal in
the majority of patients. Allogeneic hematopoietic stem cell transplantation (alloHSCT)
is the only treatment proven to cure CML, through a powerful graft versus leukemia (GvL)
effect. For patients who relapse after alloHSCT, infusions of lymphocytes from the
allogeneic donor (donor leukocyte infusion or DLI) can re-induce durable remission in
most cases, which strongly suggests that, although intrinsically resistant to
conventional chemoradiotherapy or TKI treatment, the LSCs are susceptible to
immunological targeting. It is not fully understood at the cellular level how DLI
eradicates CML stem cells. Using the retroviral bone marrow transduction/transplantation
mouse model of CML, we have established an immunotherapy model that combines the use of
TKI treatment and DLI, and is able to eradicate CML-like leukemia in >80% of
recipients. Using this platform, we aim to define the contributions of different
effector cell types within DLI, and to identify the tumor-killing mechanisms that may
provide insights in separating graft-versus-leukemia (GvL) from graft-versus-host (GvHD)
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Immunology.
Advisor: Richard Van Etten.
Committee: Fotini Gounari, Henry Wortis, Brigitte Huber, and George Daley.
Keyword: Immunology.read less