Abstract
The BCR-ABL1 fusion gene generating an oncogenic tyrosine kinase is a hallmark of chronic myeloid leukemia (CML), which can be successfully targeted by BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, treatment-free remission has been achieved in a minority of patients due to evolving TKI resistance and intolerance. Primary or acquired resistance to the approved TKIs and progression to blast crisis (BC), thus, remain a major clinical challenge that requires alternative therapeutic strategies. Here, we first demonstrate that donor natural killer (NK) cells prepared using a protocol adopted in clinical trials can efficiently eliminate CML-BC blasts, with TKI resistance regardless of BCR-ABL1 mutations, and preferentially target CD34+CD38− leukemic stem cells (LSC), a potential source of disease relapse. Mechanistically, the predominant expression of PVR, a ligand for the NK cell-activating DNAM-1 receptor, in concert with ICAM-1, a ligand for NK cell adhesion, confer this susceptibility to NK cells, despite the lack of ligands for NKG2D, a principal NK cell activating receptor, as an immune evasion mechanism. With these mechanistic insights, our findings provide a proof-of-concept that donor NK cell-based therapy is a viable strategy for overcoming TKI resistance in CML, particularly the advanced, multi-TKI-resistant CML with dismal outcome.
Highlights
Chronic myeloid leukemia (CML) results from the malignant transformation of a hematopoietic stem cell, caused by oncogenic BCR-ABL1 fusion proteins with constitutive tyrosine kinase activity.chronic myeloid leukemia (CML) usually presents at the chronic phase (CP) but, if left untreated or standard therapy fails, progresses to an accelerated phase and a terminal blast crisis (BC) with poor prognosis
To assess their susceptibility to natural killer (NK) cells, primary NK cells from healthy donors expanded using cytokines and feeder cells, a protocol adopted in clinical trials for hematological malignancies, were used as effector cells
Primary samples were obtained from CML-BC patients and healthy donors after informed consent in accordance with protocols approved by the Institutional Review Board (IRB) of Asan Medical Center and the Declaration of Helsinki
Summary
Chronic myeloid leukemia (CML) results from the malignant transformation of a hematopoietic stem cell, caused by oncogenic BCR-ABL1 fusion proteins with constitutive tyrosine kinase activity. CML usually presents at the chronic phase (CP) but, if left untreated or standard therapy fails, progresses to an accelerated phase and a terminal blast crisis (BC) with poor prognosis. Cancers 2020, 12, 1923 for CML is tyrosine kinase inhibitor (TKI) targeting BCR-ABL1, including imatinib (IM), nilotinib, and dasatinib [1]. Despite remarkable clinical responses with TKIs, the primary or acquired TKI resistance and progression to BC are major challenges limiting treatment options. TKI resistance usually occurs through the acquisition of point mutations in the BCR-ABL1 kinase domain [2]. Among the BCR-ABL1 mutations identified in relapsed CML patients, T315I mutation is frequent (20–30%)
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