MicroRNA-29b mediates altered innate immune development in acute leukemia
Bethany L. Mundy-Bosse, … , Aharon G. Freud, Michael A. Caligiuri
Bethany L. Mundy-Bosse, … , Aharon G. Freud, Michael A. Caligiuri
Published October 24, 2016
Citation Information: J Clin Invest. 2016;126(12):4404-4416. https://doi.org/10.1172/JCI85413.
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MicroRNA-29b mediates altered innate immune development in acute leukemia

Abstract

Natural killer (NK) cells can have potent antileukemic activity following haplo-mismatched, T cell–depleted stem cell transplantations for the treatment of acute myeloid leukemia (AML), but they are not successful in eradicating de novo AML. Here, we have used a mouse model of de novo AML to elucidate the mechanisms by which AML evades NK cell surveillance. NK cells in leukemic mice displayed a marked reduction in the cytolytic granules perforin and granzyme B. Further, as AML progressed, we noted the selective loss of an immature subset of NK cells in leukemic mice and in AML patients. This absence was not due to elimination by cell death or selective reduction in proliferation, but rather to the result of a block in NK cell differentiation. Indeed, NK cells from leukemic mice and humans with AML showed lower levels of TBET and EOMES, transcription factors that are critical for terminal NK cell differentiation. Further, the microRNA miR-29b, a regulator of T-bet and EOMES, was elevated in leukemic NK cells. Finally, deletion of miR-29b in NK cells reversed the depletion of this NK cell subset in leukemic mice. These results indicate that leukemic evasion of NK cell surveillance occurs through miR-mediated dysregulation of lymphocyte development, representing an additional mechanism of immune escape in cancer.

Authors

Bethany L. Mundy-Bosse, Steven D. Scoville, Li Chen, Kathleen McConnell, Hsiaoyin C. Mao, Elshafa H. Ahmed, Nicholas Zorko, Sophia Harvey, Jordan Cole, Xiaoli Zhang, Stefan Costinean, Carlo M. Croce, Karilyn Larkin, John C. Byrd, Sumithira Vasu, William Blum, Jianhua Yu, Aharon G. Freud, Michael A. Caligiuri

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Figure 2

NK cell activity is altered in leukemic mice.

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NK cell activity is altered in leukemic mice. (A) Perforin protein expre...
(A) Perforin protein expression was evaluated in freshly isolated splenic NK cells by flow cytometry (n = 5/group; **P = 0.006). (B) Granzyme B expression was measured by real-time RT-PCR on FACS-isolated NK1.1+CD3– NK cells (*P = 0.02; n = 3 mice per group, repeated 2 independent times with a representative study depicted). (C) Splenocytes were activated with anti-NK1.1 (15 μg/ml) or isotype control; labeled with anti-NK1.1, -CD3, and -CD45.1 surface antibodies; then fixed, permeabilized, and labeled with anti–IFN-γ antibody and evaluated by flow cytometry (***P = 0.004; n = 3 mice per group, 2 independent studies, representative figure shown). Student’s t test was used. (D) Proliferation was evaluated with Ki67 staining in freshly isolated splenic NK1.1+CD3– NK cells by flow cytometry (***P = 0.0001; n = 4/group, repeated 3 independent times with a representative donor depicted). (E) Nonleukemic or leukemic mice were injected with 0.5 μg IL-15. After 24 hours, organs were harvested, and proliferation was evaluated with Cell Proliferation Dye eFluor 670 within the NK1.1+CD3– cell population by flow cytometry (P < 0.01 for all organs; n = 4/group). (F) Absolute number of NK1.1+CD3– NK cells in freshly isolated spleen, blood, and bone marrow (BM) of WT or leukemic mice (**P < 0.001, ***P < 0.0001; n = 5–10 mice per group). Student’s t test was used for single comparisons; linear mixed effects models with Holm’s adjustment were used for multiple comparisons within the same mice.