Profiling of immune dysfunction in COVID-19 patients allows early prediction of disease progression.

With a rising incidence of COVID-19-associated morbidity and mortality worldwide, it is critical to elucidate the innate and adaptive immune responses that drive disease severity. We performed longitudinal immune profiling of peripheral blood mononuclear cells from 45 patients and healthy donors. We observed a dynamic immune landscape of innate and adaptive immune cells in disease progression and absolute changes of lymphocyte and myeloid cells in severe versus mild cases or healthy controls. Intubation and death were coupled with selected natural killer cell KIR receptor usage and IgM+ B cells and associated with profound CD4 and CD8 T-cell exhaustion. Pseudo-temporal reconstruction of the hierarchy of disease progression revealed dynamic time changes in the global population recapitulating individual patients and the development of an eight-marker classifier of disease severity. Estimating the effect of clinical progression on the immune response and early assessment of disease progression risks may allow implementation of tailored therapies.

Longitudinal immune profiling of mild and severe COVID-19 reveals innate and adaptive immune dysfunction and provides an early prediction tool for clinical progression.

With a rising incidence of COVID-19-associated morbidity and mortality worldwide, it is critical to elucidate the innate and adaptive immune responses that drive disease severity. We performed longitudinal immune profiling of peripheral blood mononuclear cells from 45 patients and healthy donors. We observed a dynamic immune landscape of innate and adaptive immune cells in disease progression and absolute changes of lymphocyte and myeloid cells in severe versus mild cases or healthy controls. Intubation and death were coupled with selected natural killer cell KIR receptor usage and IgM+ B cells and associated with profound CD4 and CD8 T cell exhaustion. Pseudo-temporal reconstruction of the hierarchy of disease progression revealed dynamic time changes in the global population recapitulating individual patients and the development of an eight-marker classifier of disease severity. Estimating the effect of clinical progression on the immune response and early assessment of disease progression risks may allow implementation of tailored therapies.

A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre-Clinical Discoveries.

Breast implant-associated lymphoma (BIA-ALCL) has recently been recognized as an independent peripheral T-cell lymphoma (PTCL) entity. In this study, we generated the first BIA-ALCL patient-derived tumor xenograft (PDTX) model (IL89) and a matching continuous cell line (IL89_CL#3488) to discover potential vulnerabilities and druggable targets. We characterized IL89 and IL89_CL#3488, both phenotypically and genotypically, and demonstrated that they closely resemble the matching human primary lymphoma. The tumor content underwent significant enrichment along passages, as confirmed by the increased variant allele frequency (VAF) of mutations. Known aberrations (JAK1 and KMT2C) were identified, together with novel hits, including PDGFB, PDGFRA, and SETBP1. A deep sequencing approach allowed the detection of mutations below the Whole Exome Sequencing (WES) sensitivity threshold, including JAK1G1097D, in the primary sample. RNA sequencing confirmed the expression of a signature of differentially expressed genes in BIA-ALCL. Next, we tested IL89's sensitivity to the JAK inhibitor ruxolitinib and observed a potent anti-tumor effect, both in vitro and in vivo. We also implemented a high-throughput drug screening approach to identify compounds associated with increased responses in the presence of ruxolitinib. In conclusion, these new IL89 BIA-ALCL models closely recapitulate the primary correspondent lymphoma and represent an informative platform for dissecting the molecular features of BIA-ALCL and performing pre-clinical drug discovery studies, fostering the development of new precision medicine approaches.

Chronic lymphocytic leukemia with TP53 gene alterations: a detailed clinicopathologic analysis.

TP53 alteration in chronic lymphocytic leukemia indicates a high-risk disease that is usually refractory to chemotherapy. It may be caused by deletion of 17p involving the loss of TP53 gene, which occurs in low percentage of patients at diagnosis but can be acquired as the disease progresses. Since patients may harbor TP53 mutation without chromosome 17p deletion, consensus recommendations call for both cytogenetic and PCR mutation analysis of TP53 in chronic lymphocytic leukemia. We conducted a single-institution retrospective study to investigate the clinicopathologic features of chronic lymphocytic leukemia with TP53 alterations as well as the utility of different diagnostic modalities to identify p53 alterations. Forty percent of chronic lymphocytic leukemia patients with TP53 alterations demonstrated atypical lymphocytes with cleaved/irregularly shaped nuclei and/or large atypical lymphoid cells with abundant cytoplasm in the peripheral blood. Progression was also observed in lymph node and bone marrow samples (21% with Richter transformation; 33% with findings suggestive of "accelerated phase" of chronic lymphocytic leukemia including prominent proliferation centers and/or increased numbers of prolymphocytes). However, the presence of the morphologic features suggestive of "accelerated phase" had no effect on overall survival within the chronic lymphocytic leukemia group with TP53 abnormalities (p > 0.05). As previously reported by others, a subset of patients with TP53 alterations were only identified by either PCR mutation analysis (12%) or cytogenetic studies (14%). p53 immunostain positivity was only identified in approximately half of the patients with TP53 alterations identified by either method, and it failed to identify any additional patients with p53 abnormalities. In summary, chronic lymphocytic leukemia patients with TP53 alterations frequently show atypical morphologic features. Use of multiple modalities to identify p53 abnormalities is recommended to ensure optimal sensitivity and specificity.

Histiocytic Sarcoma Following B-Lymphoblastic Leukemia/Lymphoma.

OBJECTIVES: Rare cases of clonally related histiocytic sarcoma (HS) following B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) have been reported to date. METHODS: We present a patient with HS, which appeared as a breast mass 12 months after the initial diagnosis of B-ALL. RESULTS: Both HS and the B-ALL shared IGH-MYC and IGK gene rearrangements. Next-generation sequencing and whole-exome sequencing (WES) studies detected 35 common mutations, as well as mutations unique to B-ALL (16) and HS (15), including BRAF D594G. The patient achieved complete remission of B-ALL, but HS failed to respond to many cycles of intensive chemotherapy regimens. A partial response was achieved with sorafenib, a BRAF-targeted therapy. CONCLUSIONS: To our knowledge, this is the first study to demonstrate by WES that clonally related B-ALL and HS arise through divergent evolution from a common precursor. We present our findings together with a discussion of the previously reported cases of HS in patients with B-ALL.