Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B-cell malignancy

• Published in: Blood 2022-10, Vol.140 (17), p.1858-1874
• Main Authors: Sharma, Mehul, Fu, Maggie P., Lu, Henry Y., Sharma, Ashish A., Modi, Bhavi P., Michalski, Christina, Lin, Susan, Dalmann, Joshua, Salman, Areesha, Del Bel, Kate L., Waqas, Meriam, Terry, Jefferson, Setiadi, Audi, Lavoie, Pascal M., Wasserman, Wyeth W., Mwenifumbo, Jill, Kobor, Michael S., Lee, Anna F., Kuchenbauer, Florian, Lehman, Anna, Cheng, Sylvia, Cooper, Anthony, Patel, Millan S., Turvey, Stuart E.
• Format: Article
• Language: English
• Subjects: Calcineurin - genetics; Contracture; Humans; Leukemia, B-Cell - genetics; Leukemia, B-Cell - metabolism; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - metabolism; Neoplasm Recurrence, Local; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Osteochondroma
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022015674

•Human biallelic damaging variants in NFATC2 increase susceptibility to B-cell lymphoma and musculoskeletal defects.•Studying primary human cell types lacking NFAT1 protein reveals an environment that promotes both cartilage overgrowth and lymphomagenesis. [Display omitted] The discovery of humans with monogenic disorders has a rich history of generating new insights into biology. Here we report the first human identified with complete deficiency of nuclear factor of activated T cells 1 (NFAT1). NFAT1, encoded by NFATC2, mediates calcium-calcineurin signals that drive cell activation, proliferation, and survival. The patient is homozygous for a damaging germline NFATC2 variant (c.2023_2026delTACC; p.Tyr675Thrfs∗18) and presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma. Absence of NFAT1 protein in chondrocytes caused enrichment in prosurvival and inflammatory genes. Systematic single-cell–omic analyses in PBMCs revealed an environment that promotes lymphomagenesis with accumulation of naïve B cells (enriched for oncogenic signatures MYC and JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, and aberrant CD8+ T cells. This work highlights the pleiotropic role of human NFAT1, will empower the diagnosis of additional patients with NFAT1 deficiency, and further defines the detrimental effects associated with long-term use of calcineurin inhibitors.