MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies.
Srividya SwaminathanAida S HansenLine Dam HeftdalRenumathy DhanasekaranAnja DeutzmannWadie D M FernandezDaniel F LiefwalkerCrista HortonAdriane MosleyMariola LiebersbachHolden T MaeckerDean W FelsherPublished in: Nature communications (2020)
The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt's lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.
Keyphrases
- nk cells
- diffuse large b cell lymphoma
- transcription factor
- acute lymphoblastic leukemia
- high fat diet induced
- cell therapy
- end stage renal disease
- clinical trial
- poor prognosis
- immune response
- induced apoptosis
- metabolic syndrome
- mesenchymal stem cells
- adipose tissue
- cell death
- wild type
- drug induced
- type iii
- cardiopulmonary resuscitation