Immune cells harboring somatic mutations reportedly infiltrate cancer tissues in patients with solid cancers and accompanying clonal hematopoiesis. Loss‐of‐function TET2 mutations are frequently ...observed in clonal hematopoiesis in solid cancers. Here, using a mouse lung cancer model, we evaluated the activity of Tet2‐deficient immune cells in tumor tissues. Myeloid‐specific Tet2 deficiency enhanced tumor growth in mice relative to that seen in controls. Single‐cell sequencing analysis of immune cells infiltrating tumors showed relatively high expression of S100a8/S100a9 in Tet2‐deficient myeloid subclusters. In turn, treatment with S100a8/S100a9 promoted Vegfa production by cancer cells, leading to a marked increase in the tumor vasculature in Tet2‐deficient mice relative to controls. Finally, treatment of Tet2‐deficient mice with an antibody against Emmprin, a known S100a8/S100a9 receptor, suppressed tumor growth. These data suggest that immune cells derived from TET2‐mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis and may provide a novel therapeutic target for lung cancer patients with TET2‐mutated clonal hematopoiesis.
Our study suggests that immune cells derived from TET2‐mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis. We present evidence that signaling through the S100a8/S100a9‐Emmprin‐Vegfa axis is essential for progression of a lung cancer model established in a microenvironment of Tet2‐deficient immune cells. Furthermore, we provide a novel target for lung cancer patients with accompanying TET2‐mutated clonal hematopoiesis.
Recent sequencing studies demonstrated the MYD88 L265P mutation in more than 70% of primary central nervous system lymphomas (PCNSL), and the clinical significance of this mutation has been proposed ...as diagnostic and prognostic markers in PCNSL. In contrast, mutational analyses using cell‐free DNAs have been reported in a variety of systemic lymphomas. To investigate how sensitively the MYD88 L265P mutation can be identified in cell‐free DNA from PCNSL patients, we carried out droplet digital PCR (ddPCR) and targeted deep sequencing (TDS) in 14 consecutive PCNSL patients from whom paired tumor‐derived DNA and cell‐free DNA was available at diagnosis. The MYD88 L265P mutation was found in tumor‐derived DNA from all 14 patients (14/14, 100%). In contrast, among 14 cell‐free DNAs evaluated by ddPCR (14/14) and TDS (13/14), the MYD88 L265P mutation was detected in eight out of 14 (ddPCR) and in 0 out of 13 (TDS) samples, implying dependence on the detection method. After chemotherapy, the MYD88 L265P mutation in cell‐free DNAs was traced in five patients; unexpectedly, the mutations disappeared after chemotherapy was given, and they remained undetectable in all patients. These observations suggest that ddPCR can sensitively detect the MYD88 L265P mutation in cell‐free DNA and could be used as non‐invasive diagnostics, but may not be applicable for monitoring minimal residual diseases in PCNSL.
Our findings might provide new perspectives on the utility of ddPCR‐based detection of L265P MyD88 mutations in cell‐free DNAs as a non‐invasive diagnostic marker of PCNSL.
The activities of non-haematopoietic cells (NHCs), including mesenchymal stromal cells and endothelial cells, in lymphomas are reported to underlie lymphomagenesis. However, our understanding of ...lymphoma NHCs has been hampered by unexplained NHC heterogeneity, even in normal human lymph nodes (LNs). Here we constructed a single-cell transcriptome atlas of more than 100,000 NHCs collected from 27 human samples, including LNs and various nodal lymphomas, and it revealed 30 distinct subclusters, including some that were previously unrecognized. Notably, this atlas was useful for comparative analyses with lymphoma NHCs, which revealed an unanticipated landscape of subcluster-specific changes in gene expression and interaction with malignant cells in follicular lymphoma NHCs. This facilitates our understanding of stromal remodelling in lymphoma and highlights potential clinical biomarkers. Our study largely updates NHC taxonomy in human LNs and analysis of disease status, and provides a rich resource and deeper insights into LN and lymphoma biology to advance lymphoma management and therapy.
Recent progress in next-generation sequencing technologies has shown that tumor cells in many solid cancers undergo dynamic clonal evolution. 1 Notably, diverse clones have been observed in biopsy ...samples acquired from primary or metastatic legions in solid cancers. 2-4 In contrast, intratumor heterogeneity (ITH) in lymphomas is less characterized: samples are taken only for diagnosis and multiregional sample collection is rarely performed in living patients, because chemotherapy rather than surgery is the standard treatment for most lymphoma subtypes. Black dots indicate a tumor mass; organs with red diagonal lines represent intravascular tumor invasions. kid, kidney; ll, left lung; lym, lymph node; rl1, right lung; spl, spleen. ...this analysis shows a clear phylogenic tree of aggressive lymphoma, confirming that dynamic time-dependent and spatial ITH occurs even in systemic disease.
Bing–Neel syndrome (BNS) is a rare neurologic complication of lymphoplasmacytic lymphoma (LPL) characterized by direct infiltration of lymphoplasmacytic cells (LPCs). Although no standard treatment ...has yet been established, patients with BNS harboring the
MYD88
L265P mutation have been reported to respond favorably to ibrutinib, which can cross the blood–brain barrier and trigger apoptosis of
MYD88
L265P-positive LPCs. However, it is still unclear whether monitoring of
MYD88
L265P mutation status would be useful for predicting relapse/progression or for assisting diagnosis and evaluating response to chemotherapy. Here, we report the case of a patient with BNS receiving ibrutinib in whom we detected relapse early by monitoring for molecular residual disease (MRD) based on the presence of the
MYD88
L265P mutation in cerebrospinal fluid (CSF) on droplet digital polymerase chain reaction assay. Persistent MRD increased 2 weeks before the onset of relapse symptoms without any abnormal imaging findings or evidence of clonal LPCs on CSF cytology, flow cytometry analysis, or immunofixation electrophoresis. Our findings suggest that an increase in MRD levels is correlated with relapse in patients with BNS.
Triple-negative essential thrombocythemia (ET) is a condition in which mutations in JAK2, CALR and MPL are all negative. Transformation to acute myeloid leukemia may occur during the course of ET, ...while B-acute lymphoblastic leukemia B-(ALL) is rare. We experienced a case diagnosed as B-ALL during the course of triple-negative ET. Notably, cytoreduction was required for the excessive increase in blood cells during the bone marrow recovery period after chemotherapies. Whole exome sequencing identified 17 somatic mutations: 9 were identified in both ET and B-ALL samples, while 8 were specific to B-ALL, suggesting that these 8 might have caused the transformation.
Angioimmunoblastic T-cell lymphoma (AITL) is an intractable type of T-cell lymphoma. We and others have identified that the p.Gly17Val RHOA mutation is specifically identified in AITL. We herein ...report a patient whose condition deteriorated, resulting from massive pericardial effusion one month after undergoing autologous transplantation for AITL. He was diagnosed with cardiac tamponade caused by AITL recurrence in the presence of the p.Gly17Val RHOA mutation as well as T-lineage cells with an aberrant immune-phenotype in the pericardial effusion. This case suggests that a precision medicine approach by detecting the presence of a p.Gly17Val RHOA mutation is useful for the management of AITL.
Follicular T‐cell lymphoma (FTCL) is considered to originate from follicular helper T‐cell (Tfh) cells. Angioimmunoblastic T‐cell lymphoma (AITL) and peripheral T‐cell lymphomas with the Tfh ...phenotype, derived from Tfh cells, often harbor RHOA G17V mutation. We investigated whether RHOA mutations affect the clinicopathological features of FTCL. We performed deep sequencing and Sanger sequencing for RHOA exon 2 in 16 cases of FTCL. Nine cases showed RHOA mutations, including eight with c.G50T, p.Gly17Val and one with c.G50A, p.Gly17Glu, c.A52G, p.Lys18Glu, c.T102C, p.Tyr34Tyr and c.G145T, p.Asp49Tyr. Compared to the RHOA mutation‐negative group, the RHOA mutation‐positive group had a higher tendency for B‐immunoblasts (P = 0.06), the AITL component (P = 0.09), and higher positive rate for CD10 (P = 0.09) and BCL6 (P = 0.09), and a significantly higher positive rate for CXCL13 (P = 0.04). Although not statistically significant, the RHOA mutation‐positive group showed higher values for almost all characteristic AITL features. There was no significant difference in overall survival between RHOA mutation‐positive and ‐negative groups. The RHOA mutation may play an important role in clinicopathological characteristics and lymphomagenesis of FTCL. A more detailed investigation is needed to highlight the importance of RHOA mutations in FTCL.
Cell‐free DNA (cfDNA) analysis to detect circulating tumor DNA has been focused on monitoring malignant lymphomas. However, clonal hematopoiesis of indeterminate potential (CHIP)‐associated mutations ...can also be detected by cfDNA analysis. Our aim is to investigate the origin of mutations detected in cfDNA among B‐cell lymphoma patients. MYD88/CD79B, DNMT3A, and TP53 were chosen as genes of interest, representing each of the following categories: lymphoma driver genes, CHIP‐related genes, and genes shared between lymphoma and CHIP. Seventy‐five B‐cell lymphoma patients were included in this retrospective study. Serum cfDNAs at time of complete metabolic response (CMR) were sequenced for TP53 (N = 75) and DNMT3A (N = 49). MYD88 p.L265P and CD79B p.Y196C/H mutations were analyzed in diffuse large B‐cell lymphoma (DLBCL) patients whose tumor samples were available (N = 29). Two and seven mutations in TP53 and DNMT3A, respectively, were detected in cfDNA at CMR. These mutations were detected in either bone marrow mononuclear cells (BMMC) or PBMC. Although four DNMT3A mutations were also detected in tumors, median variant allele frequencies in the tumors (<1.0%) were significantly lower than those in both BMMC (6.1%) and serum (5.2%) obtained before the therapy. Conversely, five MYD88 and three CD79B mutations detected in tumors were confirmed in cfDNA before therapy, but not in BMMC nor in cfDNA at CMR. Thus, all TP53 and DNMT3A mutations detected in cfDNA at remission seemed to originate from CHIP rather than from residual disease. Results of liquid biopsy should be carefully interpreted, especially in genes shared between lymphomas and CHIP.
Mutations detected by liquid biopsy can derive not only from tumors but also from clonal hematopoiesis in patients with lymphomas. Results of liquid biopsy should be carefully interpreted because its significance is different according to the origin of the mutations.
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