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. 2024 Jun 25;8(12):3064-3075.
doi: 10.1182/bloodadvances.2023011733.

Somatic mutations in FAS pathway increase hemophagocytic lymphohistiocytosis risk in patients with T- and/or NK-cell lymphoma

Ying Liu  1   2 , Rohan Sardana  1 , David Nemirovsky  3 , Denise Frosina  1 , Achim Jungbluth  1 , William T Johnson  4   5 , Santosha Vardhana  4   6 , Maria Arcila  1   2 , Steven M Horwitz  4   5 , Andriy Derkach  3 , Ahmet Dogan  1 , Wenbin Xiao  1
Affiliations

Somatic mutations in FAS pathway increase hemophagocytic lymphohistiocytosis risk in patients with T- and/or NK-cell lymphoma

Ying Liu et al. Blood Adv. .

Abstract

Although significant progress has been made in understanding the genetic basis of primary hemophagocytic lymphohistiocytosis (HLH), the pathogenesis of secondary HLH, the more prevalent form, remains unclear. Among the various conditions giving rise to secondary HLH, HLH in patients with lymphoma (HLH-L) accounts for a substantial proportion. In this study, we investigated the role of somatic mutations in the pathogenesis of HLH-L in a cohort of patients with T- and/or natural killer-cell lymphoma. We identified a 3-time higher frequency of mutations in FAS pathway in patients with HLH-L. Patients harboring these mutations had a 5-time increased HLH-L risk. These mutations were independently associated with inferior outcome. Hence, our study demonstrates the association between somatic mutations in FAS pathway and HLH-L. Further studies are warranted on the mechanistic role of these mutations in HLH-L.

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Conflict of interest statement

Conflict-of-interest disclosure: W.T.J. received consulting fees from Myeloid Therapeutics. S.V. served on the advisory board for Immunai and received consulting fees from ADC Therapeutics and Koch Disruptive Technologies. S.M.H. received research funding from ADC Therapeutics, Affimed, Aileron, Celgene, CRISPR Therapeutics, Daiichi Sankyo, Forty Seven Inc, Kyowa Hakko Kirin, Millennium/Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio, and consulting fees from Acrotech Biopharma, ADC Therapeutics, Astex, Auxilus Pharma, Merck, C4 Therapeutics, Celgene, Cimieo Therapeutics, Daiichi Sankyo, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, SecuraBio, Shoreline Biosciences Inc, Takeda, Trillium Therapeutics, Tubulis, Verastem/SecuraBio, Vividion Therapeutics, and Yingli Pharma Ltd. A. Dogan served as a consultant for Incyte, EUSA Pharma, and Loxo, and receives research support from Roche and Takeda. W.X. received research support from Stemline Therapeutics. The remaining authors declare no competing financial interests.

The current affiliation for R.S. is Sardana Labs, Punjab, India.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Mutational profiles between patients with and without HLH. (A) Oncoprints (only top 30 mutated genes were shown). (B) Bar plots showing the comparison of mutations in various genes. (C) Illustration of mutations in FAS pathway; figure created with BioRender.com.
Figure 2.
Figure 2.
Association of HLH risk by time-to-HLH (cumulative incidence) for patients undergoing complete HLH workup and mutations or specific T-cell malignancy. (A) Association between HLH risk and mutations of FAS, CASP8. HLA-A, CDKN1B, TP53, TNFA1P3, RARA, and STAT5B. (B) Association between HLH risk and specific T-cell malignancy.
Figure 2.
Figure 2.
Association of HLH risk by time-to-HLH (cumulative incidence) for patients undergoing complete HLH workup and mutations or specific T-cell malignancy. (A) Association between HLH risk and mutations of FAS, CASP8. HLA-A, CDKN1B, TP53, TNFA1P3, RARA, and STAT5B. (B) Association between HLH risk and specific T-cell malignancy.
Figure 3.
Figure 3.
FAS mutations in patients with T- and NK-cell lymphoma. (A) Lollipop illustration of FAS mutations in protein coding sequence (modified from cBioPortal). Red circle represents nonsense mutations; black circle represents frameshift mutations; and green circle represents missense mutations. Red arrowed line represents mutations identified in patients with HLH (only 1 patient with D260N or N264K mutations had HLH). (B-C) 3-dimensional modeling showing the amino acid changes of several representative missense mutations (https://www.ncbi.nlm.nih.gov/Structure/pdb/3OQ9). (D) Graphic illustration of the frequency of FAS mutations in patients with HLH. (E) The distribution of patients with HLH related to FAS mutations and the types of T/NK-cell lymphoma. (F) Representative pictures of FAS immunohistochemical staining in patients with T-cell lymphoma with wild-type FAS (left) and mutant FAS (right). Original magnification, 400×; scale bar, 50 mm. (G) Summary of FAS immunohistochemical staining in 48 patients with and without FAS mutations. IHC, immunohistochemistry; Mut, mutated; N, no; neg, negative; pos, positive; Y, yes.
See this image and copyright information in PMC

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