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Objective Helper innate lymphoid cells(ILCs)are recently recognized lineage negative lymphoid cells that do not express rearranged receptors and have important effector and regulatory functions in innate immunity.It can be speculated that helper ILCs and their precursors can undergo malignant transformation and it would be highly interesting to see whether some of the yet-undefined leukemias and lymphomas are in fact derived from helper ILCs.However,to our knowledge,hematologic malignancies arising from helper ILCs or ILC progenitors hasnt been reported yet.Methods Immunohistochemistry and flow cytometry analysis were used to detect the immunophenotype of this lymphoma.RNA sequencing and whole exome sequencing were used to identify possible molecular genetic changes for tumor pathogenesis.Results We reported a case of 17-year-old man with multiple lymphadenopathy that was diagnosed as lineage-negative lymphoma with a helper ILC phenotype.Histologic examination showed large monomorphic atypical lymphoid cells with prominent nucleoli and abundant eosinophilic cytoplasm scattered and patchy in distribution.Large amount of histiocytes and infiltrating lymphocytes were seen in the background(Figure 1A-1C).Immunostaining revealed positive expression of LCA(Figure 1D)and CD79a but negative for all lineage markers including B cells,T cells,NK cells,myeloid cells,stem cells,precursor cells,histiocytes,dendritic cells,mast cells and antigen receptors(Table 1).Other markers including anaplastic large cell lymphoma(ALCL)markers(CD30 and ALK),EBV-encoded small nuclear early region in situ hybridization(EBER-ISH),transcription factors(T-bet,RORγ t and Eomes),and non-lymphacytic markers(AE1/AE3,EMA,S-100,Oct 3/4,Sall4)were also negative(Table 1).IG and TCR rearrangement analysis showed proto type.Tumor cells strongly expressed helper ILC phenotypic markers such as CD127,IL-1R,GATA3,ST2,IL-17Rβ,RANKL and helper ILC produced cytokines such as IL-4 and GM-CSF(Figure 1E-1L).PD-L1/PD-L2 positive histiocytes and FOXP3 positive Tregs were seen in tumor microenvironment.Flow cytometry of bone marrow at recurrence showed positive for IL-1R and negative for T,B,NK and myelogenous lineage markers(Figure 2).TP53 sequencing showed that the exon 5 was replaced by an intergenic sequence of chromosome 21(Figure 3A and 3B)and RNA sequencing demonstrated a novel HFM1/CTD-2328D6.1 and IGLV2-14/IGLL5 gene fusion(Figure 3C and 3D).Mutations or deletions of tumor suppressor genes such as PTPRB,PPP2CB and UPK1A were found.Gene functional analysis using the Kyoto Encyclopedia of Genes and Genomes(KEGG)database showed the top 4 enrichment pathway of non-synonymous SNVs were microRNAs in cancer,ECM-receptor interaction,focal adhesion and PI3K-Akt signaling pathway.This tumor was very aggressive,resistant to chemotherapy,recurred with bone marrow involvement,and caused the death of the patient within 6 months.Conclusions To our knowledge,it is the first time to put forward hematologic malignancies that may arise from ILCs.This type of lymphoma displays many genetic alterations and immune tolerance tumor microenviroment and follows an aggressive disease course and poor prognosis.We propose negativity for lineage markers and positivity for CD127/IL-1R in combination with transcription factor expression as markers of this tumor.In the future,more cases need to be collected to clarify the nature of this disease and strengthen the awareness of this new type of lymphoma.