Characterization of IFNγ-producing natural killer cells induced by cytomegalovirus reactivation after haploidentical hematopoietic stem cell transplantation

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Fengyan Jin1, Hai Lin1, Sujun Gao1, Zheng Hu2, Song Zuo2, Liguang Sun2, Chunhui Jin1, Wei Li1, Yanping Yang1 1Department of Hematology, The First Bethune Hospital of Jilin University, Changchun, China 2Institute of Translational Medicine, The First Bethune Hospital of Jilin University, Changchun, China Correspondence to: Yanping Yang, email: yangyanping_1978@163.com Keywords: natural killer cells, interleukin, interferon-γ, NKG2D, leukemia Received: December 13, 2015 Accepted: October 26, 2016 Published: November 01, 2016

Rationale: Patients with relapsed and refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with the T315I mutation are at higher risk of relapse and have shorter overall survival. Patient concerns: A 31-year-old man presented to the hematology department with intermittent fever and pancytopenia. He was diagnosed with Ph+ acute lymphoblastic leukemia and experienced 2 relapses during treatment. A drug-resistant T315I mutation was detected in the ABL kinase region during review. Diagnoses: Morphological examination of the bone marrow revealed approximately 93.5% lymphoid blast. Flow cytometric analysis confirmed the diagnosis of common B-cell ALL with the following phenotype: CD34, CD45dim, CD19, CD10, cCD79a, CD58dim, CD81dim, cTdT, HLA-DR, CD22dim, CXCR4, CD33dim, CD20, CD25, CD13, CD123. The examination of the ABL kinase region mutation suggested a T315I mutation. Interventions: Olverembatinib, a third-generation TKI drug, was administered in combination with inotuzumab ozogamicin to treat the disease. Outcomes: The patient achieved morphological remission with a negative flow cytometry MRD test, and the quantification of BCR-ABL transcripts was 0% after 1 cycle of therapy. Lessons: The third-generation TKI olverembatinib has been proven to be effective in CML patients with the T315I mutation, and it may also be effective in Ph+ acute lymphoblastic leukemia. Some new immune drugs have also shown improvement in the remission rate. Combination therapy with olverembatinib and Ino can achieve a complete molecular response in patients with relapsed and refractory Ph+ ALL with the T315I mutation.

Natural killer (NK)‑based immunotherapeutic strategies are showing promise in the clinic, particularly against acute myeloid leukemia (AML). Similar treatments for T‑cell acute lymphoblastic leukemia (T‑ALL) have been less successful, which is due to the higher resistance of T‑ALL blasts to the cytotoxic function of NK cells. Herein, microRNA‑29b (miR‑29b) upregulation was identified in NK cells in both neurogenic locus notch homolog protein 1 (Notch1)‑T‑ALL mice and patients with T‑ALL. Furthermore, miR‑29b expression levels were downregulated in T‑ALL blast cells. In addition, there was a selective downregulation of an immature subset of NK cells, as well as a reduction in interferon γ (IFNγ) production and natural killer receptor group 2, member D (NKG2D) expression level by NK cells in Notch1‑T‑ALL mice and patients with T‑ALL. Furthermore, when miR‑29b knock‑out NK cells were adoptively transfused into Notch1‑T‑ALL mice, partial restoration of IFNγ production and NKG2D expression was observed in NK cells, accompanied by retarded ALL progression and improved survival time. These results implied that T‑ALL blast immune evasion occurred via miR‑29b‑mediated dysregulation in NK cells in the T‑ALL microenvironment.

[This corrects the article DOI: 10.3892/ol.2019.10559.].

T cell acute lymphocytic leukemia (T-ALL) is an aggressive hematologic malignancy in terms of its pathology and populations. It is important to understand the phenomenon of autofluorescence in living cells because normal and cancer cells can be distinguished by this feature.