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Acute Myeloid Leukemia Alters Group 1 Innate Lymphoid Cell Differentiation from a Common Precursor.

ABSTRACT: NK cells are known to be developmentally blocked and functionally inhibited in patients with acute myeloid leukemia (AML), resulting in poor clinical outcomes. In this study, we demonstrate that whereas NK cells are inhibited, closely related type 1 innate lymphoid cells (ILC1s) are enriched in the bone marrow of leukemic mice and in patients with AML. Because NK cells and ILC1s share a common precursor (ILCP), we asked if AML acts on the ILCP to alter developmental potential. A combination of ex vivo and in vivo studies revealed that AML skewing of the ILCP toward ILC1s and away from NK cells represented a major mechanism of ILC1 generation. This process was driven by AML-mediated activation of the aryl hydrocarbon receptor (AHR), a key transcription factor in ILCs, as inhibition of AHR led to decreased numbers of ILC1s and increased NK cells in the presence of AML. These results demonstrate a mechanism of ILC developmental skewing in AML and support further preclinical study of AHR inhibition in restoring normal NK cell development and function in the setting of AML.

SUBMITTER: Lordo MR

PROVIDER: S-EPMC8429221 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Acute Myeloid Leukemia Alters Group 1 Innate Lymphoid Cell Differentiation from a Common Precursor.

Lordo Matthew R MR Wu Kevin G KG Altynova Ekaterina E Shilo Nikolas N Kronen Parker P Nalin Ansel P AP Weigel Christoph C Zhang Xiaoli X Yu Jianhua J Oakes Christopher C CC Caligiuri Michael A MA Freud Aharon G AG Mundy-Bosse Bethany L BL

Journal of immunology (Baltimore, Md. : 1950) 20210820 6

NK cells are known to be developmentally blocked and functionally inhibited in patients with acute myeloid leukemia (AML), resulting in poor clinical outcomes. In this study, we demonstrate that whereas NK cells are inhibited, closely related type 1 innate lymphoid cells (ILC1s) are enriched in the bone marrow of leukemic mice and in patients with AML. Because NK cells and ILC1s share a common precursor (ILCP), we asked if AML acts on the ILCP to alter developmental potential. A combination of e ...[more]

PMID: 34417259

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Project description:Background:A new regulatory subpopulation of ILCs, ILCreg has been identified in mouse and human intestines. ILCregs share characteristics with both innate lymphoid cells and regulatory cells; however, the significance of CD45+Lin-CD127+IL-10+ ILCregs in patients with AML remains unclear. Intriguingly, ILCregs constitutively express id2, id3, sox4, tgfbr1, tgfbr2, il2rb and il2rg, but the significance of miRNAs associated with these genes has yet to be explored. In this study, we evaluate ILCreg frequency, ILCreg gene-associated miRNA quantification, and its significance in patients with AML and normal donors. Methods:Using 4 color combinations of surface and intracellular antibody staining, the CD45+Lin-CD127+IL-10+ ILCregs from 12 normal donors and 42 patients newly diagnosed with AML were measured by flow cytometry. Plasma samples and bone marrow cells from 6 normal donors and 9 patients with AML were studied by next-generation sequence miRNAs quantification. Results:Our results showed that the frequency of ILCregs was 0.8924±1.3791% in bone marrow (BM) cells from normal donors and 0.2434±0.5344% in BM cells from AML patients. The frequency of ILCreg cells in AML patients was significantly lower than that in normal donors (P<0.01). Furthermore, the frequency of the CD45+Lin-CD127+IL-10- subset was 4.0869±6.7701% and 0.2769±0.2526% from normal donors and AML patients, respectively. There was a statistically significant difference of CD45+Lin-CD127+IL-10- cells between normal donors and AML patients (p<0.01). miRNA detection results showed 376 miRNAs from plasma and 182 miRNAs from BM cell samples with expression levels with a statistically significant difference between AML patients and normal donors (both Q and P-value < 0.001). Analysis of miRNAs from ILCregs associated genes including id2, id3, sox4, tgfbr1, tgfbr2, il2rb, and il3rg, from normal donors and AML patients demonstrated 34 miRNA from plasma samples and 14 miRNA segments from BM cell samples with a statistically significant difference between AML patients and normal donors (both Q and P-value <0.001). Among them, 4 miRNAs (hsa-miR-193b-3p, hsa-miR-1270, hsa-miR-210-3p, and hsa-miR-486-3p) were detected in both plasma and BM cell samples. Conclusion:Our study enumerated ILCregs, then measured miRNAs from those ILCregs in AML samples for the first time. The results demonstrated the deficiency of ILCreg and differential expression of miRNAs in patients with AML.

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Acute Myeloid Leukemia Alters Group 1 Innate Lymphoid Cell Differentiation from a Common Precursor.

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Acute Myeloid Leukemia Alters Group 1 Innate Lymphoid Cell Differentiation from a Common Precursor.

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