Language：Others   Publishing type：Research paper (scientific journal)   Publisher：American Society of Clinical Oncology (ASCO)  

PURPOSE

The impact of genomic alterations on response and resistance to trastuzumab deruxtecan (T-DXd) has not been elucidated. Thus, we sought to identify factors predicting sensitivity to T-DXd in gastric or gastroesophageal junction (G/GEJ) cancer.

METHODS

We conducted a retrospective study using real-world clinical data and next-generation sequencing–based comprehensive genomic profiling (CGP) data from patients with advanced G/GEJ cancers, collected by the nationwide database in Japan. We analyzed the associations between genomic alterations and the patients' survivals after T-DXd treatment.

RESULTS

In 114 patients with human epidermal growth factor receptor-2 (HER2)–positive G/GEJ cancer treated with T-DXd, the most frequently altered genes were TP53 (82%), ERBB2 (80%), and CCNE1 (36%). Multivariate Cox regression analysis revealed CCNE1 amplification to be a significant predictor of shorter progression-free survival (PFS) after T-DXd treatment among 91 patients whose CGP samples were obtained before T-DXd (median PFS, 131 days v 189 days; hazard ratio [HR], 1.90 [95% CI, 1.02 to 3.53]; P = .044). Analyses of 1,450 G/GEJ cancers revealed significant CCNE1/ ERBB2 coamplification (41% relative to 11% CCNE1 amplification in ERBB2-nonamplified tumors; P < .0001). ERBB2-activating mutations were also detected in 3.7% of G/GEJ cancers and in 8.8% of HER2-positive G/GEJ cancers treated with T-DXd. Patients with ERBB2-mutated tumors showed shorter PFS than those without ERBB2 mutations after T-DXd treatment (mPFS, 105 v 180 days; P = .046).

CONCLUSION

CCNE1 amplification may confer primary resistance to T-DXd in HER2-positive G/GEJ cancer, suggesting that the cell cycle could be a potential therapeutic target in CCNE1/ERBB2 coamplified tumors. ERBB2-activating mutation may also attenuate T-DXd efficacy in HER2-positive G/GEJ cancer.

DOI： 10.1200/po.23.00681

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It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here we performed targeted-capture sequencing using bone marrow plasma cells (BMPC) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, while KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the six relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥ 2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index (ctRRMM-PI), classifying patients into three categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM.

DOI： 10.1182/blood.2023022540

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：JAMA Oncology  

<h4>Importance</h4>Substantial heterogeneity exists in treatment recommendations across molecular tumor boards (MTBs), especially for biomarkers with low evidence levels; therefore, the learning program is essential.<h4>Objective</h4>To determine whether a learning program sharing treatment recommendations for biomarkers with low evidence levels contributes to the standardization of MTBs and to investigate the efficacy of an artificial intelligence (AI)-based annotation system.<h4>Design, setting, and participants</h4>This prospective quality improvement study used 50 simulated cases to assess concordance of treatment recommendations between a central committee and participants. Forty-seven participants applied from April 7 to May 13, 2021. Fifty simulated cases were randomly divided into prelearning and postlearning evaluation groups to assess similar concordance based on previous investigations. Participants included MTBs at hub hospitals, treating physicians at core hospitals, and AI systems. Each participant made treatment recommendations for each prelearning case from registration to June 30, 2021; participated in the learning program on July 18, 2021; and made treatment recommendations for each postlearning case from August 3 to September 30, 2021. Data were analyzed from September 2 to December 10, 2021.<h4>Exposures</h4>The learning program shared the methodology of making appropriate treatment recommendations, especially for biomarkers with low evidence levels.<h4>Main outcomes and measures</h4>The primary end point was the proportion of MTBs that met prespecified accreditation criteria for postlearning evaluations (approximately 90% concordance with high evidence levels and approximately 40% with low evidence levels). Key secondary end points were chronological enhancements in the concordance of treatment recommendations on postlearning evaluations from prelearning evaluations. Concordance of treatment recommendations by an AI system was an exploratory end point.<h4>Results</h4>Of the 47 participants who applied, 42 were eligible. The accreditation rate of the MTBs was 55.6% (95% CI, 35.3%-74.5%; P < .001). Concordance in MTBs increased from 58.7% (95% CI, 52.8%-64.4%) to 67.9% (95% CI, 61.0%-74.1%) (odds ratio, 1.40 [95% CI, 1.06-1.86]; P = .02). In postlearning evaluations, the concordance of treatment recommendations by the AI system was significantly higher than that of MTBs (88.0% [95% CI, 68.7%-96.1%]; P = .03).<h4>Conclusions and relevance</h4>The findings of this quality improvement study suggest that use of a learning program improved the concordance of treatment recommendations provided by MTBs to central ones. Treatment recommendations made by an AI system showed higher concordance than that for MTBs, indicating the potential clinical utility of the AI system.

DOI： 10.1001/jamaoncol.2023.5120

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Annals of Hematology  

Real-world studies permit inclusion of a more diverse patient population and provide more information on the effectiveness of treatments used in routine clinical practice. This prospective, multicenter, observational study investigated the effectiveness and safety of ixazomib plus lenalidomide and dexamethasone (IRd) in 295 patients with relapsed/refractory multiple myeloma (RRMM) in routine clinical practice in Japan. Patients had a median age of 74 years, 80.0% were aged ≥ 65 years, 42.0% had received ≥ 3 lines of prior treatment, and 28.5% were "frail" according to the International Myeloma Working Group frailty score. After a median follow-up of 25.0 months, median progression-free survival (PFS) was 15.3 (95% CI 12.4-19.5) months, while median overall survival was not reached. The overall response rate was 53.9%, and 31.5% of patients had a very good partial response or better. In the subgroup analysis, median PFS was better in patients with 1 versus 2 or ≥ 3 lines of prior treatment (29.0 vs 19.2 or 6.9 months) and paraprotein versus clinical relapse (16.0 vs 7.9 months), but median PFS was not notably affected by frailty score or age group. Dose adjustment was more frequent among patients aged > 75 years, especially early after IRd treatment initiation. Treatment-emergent adverse events (TEAEs) of any grade occurred in 84.4% of patients and 24.7% of patients discontinued treatment due to TEAEs; no new safety concerns were found. These findings suggest that oral IRd triplet regimen is an effective and tolerable treatment option for RRMM patients in real-world settings outside of clinical trials.ClinicalTrials.gov identifier: NCT03433001; Date of registration: 14 February 2018.

DOI： 10.1007/s00277-023-05428-7

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Language：English   Publisher：Cancer Medicine  

Background: Anti-PD-1-based immunotherapy is considered a preferred first-line treatment for advanced BRAF V600-mutant melanoma. However, a recent international multi-center study suggested that the efficacy of immunotherapy is poorer in Asian patients in the non-acral cutaneous subtype. We hypothesized that the optimal first-line treatment for Asian patients may be different. Methods: We retrospectively collected data of Asian patients with advanced BRAF V600-mutant melanoma treated with first-line BRAF/MEK inhibitors (BRAF/MEKi), anti-PD-1 monotherapy (Anti-PD-1), and nivolumab plus ipilimumab (PD-1/CTLA-4) between 2016 and 2021 from 28 institutions in Japan. Results: We identified 336 patients treated with BRAF/MEKi (n = 236), Anti-PD-1 (n = 64) and PD-1/CTLA-4 (n = 36). The median follow-up duration was 19.9 months for all patients and 28.6 months for the 184 pa tients who were alive at their last follow-up. For patients treated with BRAF/MEKi, anti-PD-1, PD-1/CTLA-4, the median ages at baseline were 62, 62, and 53 years (p = 0.03); objective response rates were 69%, 27%, and 28% (p < 0.001); median progression-free survival (PFS) was 14.7, 5.4, and 5.8 months (p = 0.003), and median overall survival (OS) was 34.6, 37.0 months, and not reached, respectively (p = 0.535). In multivariable analysis, hazard ratios (HRs) for PFS of Anti-PD-1 and PD-1/CTLA-4 compared with BRAF/MEKi were 2.30 (p < 0.001) and 1.38 (p = 0.147), and for OS, HRs were 1.37 (p = 0.111) and 0.56 (p = 0.075), respectively. In propensity-score matching, BRAF/MEKi showed a tendency for longer PFS and equivalent OS with PD-1/CTLA-4 (HRs for PD-1/CTLA-4 were 1.78 [p = 0.149]) and 1.03 [p = 0.953], respectively). For patients who received second-line treatment, BRAF/MEKi followed by PD-1/CTLA-4 showed poor survival outcomes. Conclusions: The superiority of PD-1/CTLA-4 over BRAF/MEKi appears modest in Asian patients. First-line BRAF/MEKi remains feasible, but it is difficult to salvage at progression. Ethnicity should be considered when selecting systemic therapies until personalized biomarkers are available in daily practice. Further studies are needed to establish the optimal treatment sequence for Asian patients.

DOI： 10.1002/cam4.6438

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DOI： 10.1182/blood.2023020923

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Nature Communications  

Changes in the transcriptional machinery cause aberrant self-renewal of non-stem hematopoietic progenitors. AF10 fusions, such as CALM-AF10, are generated via chromosomal translocations, causing malignant leukemia. In this study, we demonstrate that AF10 fusion proteins cause aberrant self-renewal via ENL, which binds to MOZ/MORF lysine acetyltransferases (KATs). The interaction of ENL with MOZ, via its YEATS domain, is critical for CALM-AF10-mediated leukemic transformation. The MOZ/ENL complex recruits DOT1L/AF10 fusion complexes and maintains their chromatin retention via KAT activity. Therefore, inhibitors of MOZ/MORF KATs directly suppress the functions of AF10 fusion proteins, thereby exhibiting strong antitumor effects on AF10 translocation-induced leukemia. Combinatorial inhibition of MOZ/MORF and DOT1L cooperatively induces differentiation of CALM-AF10-leukemia cells. These results reveal roles for the MOZ/ENL complex as an essential recruiting factor of the AF10 fusion/DOT1L complex, providing a rationale for using MOZ/MORF KAT inhibitors in AF10 translocation-induced leukemia.

DOI： 10.1038/s41467-023-37712-5

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Leukemia  

To identify molecules/pathways governing Venetoclax (VEN) sensitivity, we performed genome-wide CRISPR/Cas9 screens using a mouse AML line insensitive to VEN-induced mitochondrial apoptosis. Levels of sgRNAs targeting March5, Ube2j2 or Ube2k significantly decreased upon VEN treatment, suggesting synthetic lethal interaction. Depletion of either Ube2j2 or Ube2k sensitized AML cells to VEN only in the presence of March5, suggesting coordinate function of the E2s Ube2j2 and Ube2k with the E3 ligase March5. We next performed CRISPR screens using March5 knockout cells and identified Noxa as a key March5 substrate. Mechanistically, Bax released from Bcl2 upon VEN treatment was entrapped by Mcl1 and Bcl-XL and failed to induce apoptosis in March5 intact AML cells. By contrast, in March5 knockout cells, liberated Bax did not bind to Mcl1, as Noxa likely occupied Mcl1 BH3-binding grooves and efficiently induced mitochondrial apoptosis. We reveal molecular mechanisms underlying AML cell-intrinsic VEN resistance and suggest a novel means to sensitize AML cells to VEN.

DOI： 10.1038/s41375-023-01879-z

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The cancer stem cell (CSC) theory features typically rare self-renewing subpopulation that reconstitute the heterogeneous tumor. Identification of molecules which characterize the feature of CSCs is a key imperative for further understanding of tumor heterogeneity and for the development of novel therapeutic strategies. However, the use of conventional markers of CSCs is still insufficient for the isolation of bona fide CSCs. We investigated organoids which are miniature forms of tumor tissues with reconstructing cellular diversity to identify specific marker to characterize CSCs in heterogeneous tumors. Here, we report that receptor for hyaluronan-mediated motility (RHAMM) expresses in a subpopulation of CD44+ conventional human colorectal CSC fraction. Single-cell transcriptomics of organoids highlighted RHAMM positive proliferative cells that revealed distinct characteristics among the various cell types. Prospectively isolated RHAMM+ CD44+ cells from the human colorectal cancer tissues showed highly proliferative character with self-renewal ability in comparison with the other cancer cells. Furthermore, inhibition of RHAMM strongly suppressed organoids formation in vitro and inhibited the tumor growth in vivo. Our findings suggest that RHAMM is a potential therapeutic target because it is a specific marker of the proliferative subpopulation within the conventional CSC fraction.

DOI： 10.1111/cas.15795

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Language：English   Publisher：(一社)日本血液学会  

症例は31歳女性で、inv(16)(p13.1q22)を有する急性骨髄性白血病(AML)と診断された。臨床試験で自家造血幹細胞移植(ASCT)後に大量化学療法を受けたが、ASCTから2年後に再発した。そこで、HLA一致の非血縁者男性ドナーから、強度減弱前処置を用いた同種造血幹細胞移植(HSCT)を受けた。タクロリムス(Tac)とメトトレキサートによる予防下で急性移植片対宿主病(GVHD)発症したため、プレドニゾロン(PSL)で対処した。その後、中等度の慢性GVHDに進行したため、PSLとリツキシマブによる追加の免疫抑制剤、および修正フルチカゾン/アリスロマイシン/モンテルカスト(mFAM)併用療法を施行した。慢性GVHDに対してTac療法とmFAM療法を継続していたが、同種HSCT後9年目に食欲不振、寝汗、右下腹部痛を呈した。ドナー由来のバーキットリンパ腫と診断した。リツキシマブ併用集中化学療法により部分奏効が得られた。再発リスクの低減と化学療法の反復による臓器毒性を回避するため、アップフロント大量化学療法後にドナー由来のCD34+細胞を用いた幹細胞救済療法(疑似自家造血幹細胞移植[pASCT])を施行し、免疫抑制剤を適切に調整した。pASCT後23ヵ月間、cGVHDの増悪もなく、無病状態が維持された。

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DOI： 10.1001/jamanetworkopen.2022.45081

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

厚生労働省より指定を受けたがんゲノム医療中核拠点病院におけるprecision oncologyの実施状況を調査した。第1期(11病院、2019年6月～2020年1月)と第2期(12病院、2020年2月～2021年1月)に包括的ゲノムプロファイリング(CGP)検査を受けた患者は、それぞれ754例と2294例であり、そのうち28例(3.7%)と176例(7.7%)がゲノムベースの治療を受けた(p<0.001)。さらに、第1期と第2期でそれぞれ25例(3.3%)と237例(10.3%)が遺伝カウンセリングを受けるよう勧められた(p<0.001)。遺伝カウンセリングを受けるよう勧められた症例の割合は、腫瘍のみの解析の方が腫瘍と正常のペア解析よりも高かったが(10.0% vs. 3.5%)、実際の相談率はペア解析の方が腫瘍のみの解析よりも高かった(82.6% vs. 51.5%)。以上より、ネットワーク化された分子腫瘍ボードにおいて利用可能な臨床試験に関する推奨が、ゲノムベース治療の増加に寄与する可能性、また腫瘍のみの検査ではなく腫瘍と正常のペア検査が遺伝カウンセリングのための患者紹介の効率を高める可能性が示唆された。

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DOI： 10.1111/cas.15517

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Donor-derived hematological malignancies have been recognized as rare but serious late complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Most cases in the literature were diagnosed as myelodysplastic syndrome or acute leukemia, with very few malignant lymphoma reported. We herein present another case of donor-derived Burkitt lymphoma that occurred 9 years after allo-HSCT under continued administration of immunosuppressants for chronic graft-versus-host disease (GVHD). The patient achieved a partial response after rituximab-combined intensive chemotherapy. To reduce the risk of relapse and to avoid organ toxicities due to repeated chemotherapies, we performed upfront high-dose chemotherapy followed by stem cell rescue using donor-derived CD34⁺ cells, called pseudo-autologous HSCT (pASCT), and adjusted immunosuppressants appropriately. The patient remained disease-free for 23 months after pASCT without exacerbation of cGVHD. Although the observation period has been relatively short and longer follow-up is needed, pASCT may be a feasible option for donor-derived lymphoma even in patients with active cGVHD.

DOI： 10.1007/s12185-022-03458-x

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Other Link： https://link.springer.com/article/10.1007/s12185-022-03458-x/fulltext.html

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<h4>Background</h4>Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development.<h4>Methods</h4>To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO).<h4>Results</h4>CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area.<h4>Conclusions</h4>E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.

DOI： 10.1007/s10120-022-01307-8

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Comprehensive genomic profiling is increasingly used to facilitate precision oncology based on molecular stratification. In addition to conventional tissue comprehensive genomic profiling, comprehensive genomic profiling of circulating tumor DNA has become widely utilized in cancer care owing on its advantages, including less invasiveness, rapid turnaround time, and capturing heterogeneity. However, circulating tumor DNA comprehensive genomic profiling has some limitations, mainly false negatives due to low levels of plasma circulating tumor deoxyribonucleic acid and false positives caused by clonal hematopoiesis. Nevertheless, no guidelines and recommendations fully address these issues. Here, an expert panel committee involving representatives from 12 Designated Core Hospitals for Cancer Genomic Medicine in Japan was organized to develop expert consensus recommendations for the use of circulating tumor deoxyribonucleic acid-based comprehensive genomic profiling. The aim was to generate guidelines for clinicians and allied healthcare professionals on the optimal use of the circulating tumor DNA assays in advanced solid tumors and to aid the design of future clinical trials that utilize and develop circulating tumor DNA assays to refine precision oncology. Fourteen clinical questions regarding circulating tumor deoxyribonucleic acid comprehensive genomic profiling including the timing of testing and considerations for interpreting results were established by searching and curating associated literatures, and corresponding recommendations were prepared based on the literature for each clinical question. Final consensus recommendations were developed by voting to determine the level of each recommendation by the committee members.

DOI： 10.1111/cas.15504

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

E-カドヘリン欠損胃印環細胞癌(SRCC)における新規治療標的を同定することを目的とした。E-カドヘリンをコードするCDH1遺伝子をノックアウト(KO)したヒト胃オルガノイド(hGO)を用いて、in vitroのE-カドヘリン欠損胃癌モデルを作製し、新規治療標的を探索した。CDH1 KO hGO細胞は、SRCCに類似した特徴的な形態変化と高い細胞運動性を示した。RNA配列解析の結果、CDH1 KO hGO細胞では、野生型と比較して、マトリックスメタロプロテアーゼ(MMP)遺伝子の発現が増加していた。MMP阻害剤は、in vitroでCDH1 KO hGO細胞およびSRCC細胞株の細胞運動を抑制した。95例の臨床胃癌組織を用いた免疫蛍光分析により、MMP-3はE-カドヘリン異常のSRCCに特異的に多く存在することが示された。また、CDH1 KO後、CXCR4分子が細胞膜上に移行した。CXCR4のリガンドであるCXCL12を培養液に添加すると、CDH1 KO hGO細胞の細胞生存率が延長し、CXCR4アンタゴニストであるAMD3100によってその効果が消失した。SRCCの臨床サンプルでは、CXCL12を分泌する線維芽細胞が癌領域に著しく浸潤していることを確認した。以上より、MMPとCXCL12/CXCR4軸は、E-カドヘリン欠損SRCCの新規治療標的として有望な候補であると考えられた。

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DOI： 10.1002/pbc.29915

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

The RNA decapping scavenger protein, DcpS, has recently been identified as a dependency in acute myeloid leukemia (AML). The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by DcpS modulation. Considering this strong DcpS dependence in AML cell lines, we explored PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, a PROTAC exhibiting effective degradation of DcpS at nanomolar concentrations. JCS-1 non-covalently binds DcpS with a RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and sustained DcpS degradation in several AML cell lines. JCS-1 serves as a chemical biology tool to interrogate DcpS degradation and associated changes in RNA processes in different cellular contexts, which may be an attractive strategy for the treatment of AML and other DcpS-dependent genetic disorders.

DOI： 10.1021/acschembio.2c00145

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Language：English   Publisher：Elsevier  

Clonal hematopoiesis (CH) refers to the disproportionate expansion of hematopoietic stem cell clones and their corresponding progeny following the acquisition of somatic mutations. CH is common at the time of diagnosis in patients with blood cancers, including multiple myeloma (MM) and lymphoma. The presence of CH mutations correlates with IL-6 mediated inflammation and may result in lymphoma or MM modulation through microenvironment effects or by manifestations of the mutations themselves within the founding tumor clone. As might be expected with a variety of mutations and multiple potential mechanisms, CH exerts context-dependent effects, being protective in some settings and harmful in others. Though CH is very common in patients with hematologic malignancies, how it intersects with therapy and the natural disease course of these cancers are active areas of investigation. In lymphomas and MM specifically, patients have high rates of CH at diagnosis and are subsequently exposed to therapies, such as cytotoxic chemotherapy, that can cause CH progression to overt hematologic malignancy. The expanding diversity of treatment modalities for these cancers also increases the opportunities for CH to impact clinical outcome and modulate clinical responses. Here we review the basic biology and known health effects of CH, and we focus on the clinical relevance of CH in lymphoma and MM.

DOI： 10.1016/j.jaccao.2022.01.098

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DOI： 10.1007/s12185-021-03191-x

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Blood Advances  

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy, with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin (COO), genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of “unfavorable” molecular signatures.

DOI： 10.1182/bloodadvances.2021004618

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Blood  

Acute lymphoblastic leukemia (ALL) harboring the IgH-CRLF2 rearrangement (IgH-CRLF2-r) exhibits poor clinical outcomes and is the most common subtype of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). While multiple chemotherapeutic regimens, including ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. To identify molecules/pathways relevant for IgH-CRLF2-r ALL pathogenesis, we performed genome-wide CRISPR-Cas9 dropout screens in the presence or absence of ruxolitinib using 2 IgH-CRLF2-r ALL lines that differ in RAS mutational status. To do so, we employed a baboon envelope pseudotyped lentiviral vector system, which enabled, for the first time, highly efficient transduction of human B cells. While single-guide RNAs (sgRNAs) targeting CRLF2, IL7RA, or JAK1/2 significantly affected cell fitness in both lines, those targeting STAT5A, STAT5B, or STAT3 did not, suggesting that STAT signaling is largely dispensable for IgH-CRLF2-r ALL cell survival. We show that regulators of RAS signaling are critical for cell fitness and ruxolitinib sensitivity and that CRKL depletion enhances ruxolitinib sensitivity in RAS wild-type (WT) cells. Gilteritinib, a pan-tyrosine kinase inhibitor that blocks CRKL phosphorylation, effectively killed RAS WT IgH-CRLF2-r ALL cells in vitro and in vivo, either alone or combined with ruxolitinib. We further show that combining gilteritinib with trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status. Our study delineates molecules/pathways relevant for CRLF2-r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes.

DOI： 10.1182/blood.2021012976

Web of Science

Scopus

PubMed

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12185-021-03207-6

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.

DOI： 10.1038/s41375-021-01369-0

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Other Link： https://www.nature.com/articles/s41375-021-01369-0

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/jca.21917

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10147-020-01844-1

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12185-021-03116-8

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12185-020-03006-5

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00277-020-04310-0

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1182/blood.2019003749

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1182/blood.2019002194

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1158/1535-7163.mct-18-1216

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41409-019-0486-4

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41588-019-0453-4

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/bioinformatics/bty913

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41375-018-0253-3

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41388-018-0480-0

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/10428194.2018.1466295

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbmt.2018.07.017

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13059-018-1563-5

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbmt.2018.06.002

Language：Others   Publishing type：Research paper (scientific journal)  

<title>Key Points</title>
Microenvironmental immune cell signatures stratify PTCL-NOS patients into clinically meaningful disease subtypes. Immune-checkpoint inhibitors represent potential therapeutic options for a PTCL-NOS patient subgroup.

DOI： 10.1182/bloodadvances.2018018754

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/10428194.2017.1403021

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ccell.2018.01.012

Language：Others   Publishing type：Research paper (scientific journal)  

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

DOI： 10.1182/blood-2016-09-741611

Language：Others   Publishing type：Research paper (scientific journal)  

Heme is required for survival of all cells, and in most eukaryotes, is produced through a series of eight enzymatic reactions. Although heme production is critical for many cellular processes, how it is coupled to cellular differentiation is unknown. Here, using zebrafish, murine, and human models, we show that erythropoietin (EPO) signaling, together with the GATA1 transcriptional target, <italic>AKAP10</italic>, regulates heme biosynthesis during erythropoiesis at the outer mitochondrial membrane. This integrated pathway culminates with the direct phosphorylation of the crucial heme biosynthetic enzyme, ferrochelatase (FECH) by protein kinase A (PKA). Biochemical, pharmacological, and genetic inhibition of this signaling pathway result in a block in hemoglobin production and concomitant intracellular accumulation of protoporphyrin intermediates. Broadly, our results implicate aberrant PKA signaling in the pathogenesis of hematologic diseases. We propose a unifying model in which the erythroid transcriptional program works in concert with post-translational mechanisms to regulate heme metabolism during normal development.

DOI： 10.7554/elife.24767

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1126/science.aad3312

Language：Others   Publishing type：Research paper (scientific journal)  

<title>Abstract</title>
Acquisition of the arterial and haemogenic endothelium fates concurrently occur in the aorta–gonad–mesonephros (AGM) region prior to haematopoietic stem cell (HSC) generation. The arterial programme depends on Dll4 and the haemogenic endothelium/HSC on Jag1-mediated Notch1 signalling. How Notch1 distinguishes and executes these different programmes in response to particular ligands is poorly understood. By using two Notch1 activation trap mouse models with different sensitivity, here we show that arterial endothelial cells and HSCs originate from distinct precursors, characterized by different Notch1 signal strengths. Microarray analysis on AGM subpopulations demonstrates that the Jag1 ligand stimulates low Notch strength, inhibits the endothelial programme and is permissive for HSC specification. In the absence of Jag1, endothelial cells experience high Dll4-induced Notch activity and select the endothelial programme, thus precluding HSC formation. Interference with the Dll4 signal by ligand-specific blocking antibodies is sufficient to inhibit the endothelial programme and favour specification of the haematopoietic lineage.

DOI： 10.1038/ncomms9510

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/nature15521

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/nn.4025

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.3324/haematol.2014.119537

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1158/2159-8290.cd-14-1022

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1074/jbc.m114.564625

Language：Others   Publishing type：Research paper (scientific journal)  

Classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) are considered separate entities with different prognosis and treatment. However, morphologic features can be similar and immunohistochemical studies are essential in the distinction; thus, determination of additional biomarkers is of utmost importance. LRF/Pokemon is a proto-oncogene, an interacting partner co-expressed with BCL6 in germinal centers and highly expressed in diffuse large B-cell lymphoma and follicular lymphoma. Conversely, loss of the LRF gene in mouse hematopoietic stem cells results in complete block of early B cell development with concomitant Notch de-repression, indicating its critical role in B versus T cell fate decision at the hematopoietic stem cell stage. For the first time, we show that LRF/Pokemon is predominantly expressed in NLPHL cases as is BCL6 with low to absent NOTCH1 protein expression; while Hodgkin Reed-Sternberg (HRS) cells in CHL show low to absent BCL6 and LRF/Pokemon expression with higher NOTCH1 expression. We illustrate a potential functional interaction between LRF and BCL6 in NLPHL pathogenesis, and differential expression of LRF/Pokemon and NOTCH1 proteins in CHL thus showing differential expression, making for an additional diagnostic marker and therapeutic target.

DOI： 10.1177/1066896913513833

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.cmet.2013.01.013

Language：Others   Publishing type：Research paper (scientific journal)  

<title>Key Points</title>
Notch1/DII4-mediated signals are normally suppressed by LRF, preventing HSCs from premature T-cell differentiation in the bone marrow. Erythroblastic islands may have the capacity to regulate the fate and function of HSCs.

DOI： 10.1182/blood-2012-03-418103

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ccr.2012.02.018

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1073/pnas.1116042109

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1172/jci45682

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.devcel.2009.09.005

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1126/science.1140881

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/nature03203

Language：Others   Publishing type：Research paper (scientific journal)  

The zinc finger transcription factor GATA-2 plays a critical role in the survival and proliferation of hematopoietic stem cells. This study examined the interaction of GATA-2 with histone deacetylases (HDACs) to define the involvement of HDACs in the regulation of GATA-2 function. GATA-2 directly associates with HDAC3 but not with HDAC1. Consistent with this, HDAC3 suppressed the transcriptional potential of GATA-2, whereas HDAC1 did not affect GATA-2–dependent transcription. Results further demonstrated that GATA-2 and HDAC3 colocalized in the nucleus. These results identify GATA-2 as a nuclear target for HDAC3-mediated repression. Furthermore, GATA-2 also directly associated with HDAC5 but not with other class II HDACs examined, that is, HDAC4 and HDAC6. This is the first demonstration that a tissue-specific transcription factor directly and selectively interacts with HDAC3 and HDAC5 among HDAC family members.

DOI： 10.1182/blood.v98.7.2116

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1006/bbrc.2001.4840

Language：Others   Publishing type：Research paper (scientific journal)  

Histone deacetylase inhibitors (HDACIs) have been used to focus on the effects of inducing gene expression through the acetylation of histones which results in chromatin remodeling. The study explored whether HDACIs could induce the expression of costimulatory/adhesion molecules on acute myeloid leukemia (AML) cells, thereby effectively inducing tumor immunity. The expression of CD80, CD86, human leukocyte antigen (HLA)-DR, HLA-ABC, and intracellular adhesion molecule-1 (ICAM-1) was tested in human AML cell lines after the addition of HDACI, sodium butyrate (SB). Generally, increased expression of CD86 was observed by SB treatment in a majority of cell lines, and ICAM-1 was expressed in fewer cell lines. Essentially the same results were obtained using other HDACIs such as FR901228, trichostatin A, and trapoxin A. Quantitation of transcripts of CD86 accompanied with RNA synthesis inhibition assay and nuclear run-on assay revealed that SB up-regulates the CD86 expression transcriptionally. Furthermore, chromatin immunoprecipitation experiments showed that HDACI treatment caused remarkable acetylation on histone H3 and H4 at CD86 promoter chromatin in vivo. In 30 clinical AML samples, CD86 expression was significantly increased (P <.001) by SB treatment, and the expression of HLA-DR and ICAM-1 was moderately increased (P <.05) by SB treatment. Finally, the allogeneic mixed leukocyte reaction (allo-MLR) against HL60 cells pretreated with SB was enhanced 4-fold compared with allo-MLR obtained with non-treated HL60 cells. These results suggest that the immunotherapeutic use of HDACIs may become a novel tool for treatment of AML. (Blood. 2000;96:3847-3856)

Event date： 2023.12 - 2022.12

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Event date： 2023.9

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Event date： 2021.12

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Venue：Atlanta   Country：United States  

Event date： 2019.9 - 2020.7

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Venue：Orlando, FL.   Country：United States  

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Venue：Orlando, FL.   Country：United States  

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Venue：Orlando, FL.   Country：United States  

Event date： 2023.3

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Event date： 2019.9 - 2020.7

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Venue：Orlando, FL.   Country：United States  

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Venue：Houston, TX.   Country：United States  

Event date： 2019.9 - 2020.7

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Venue：Houston, TX.   Country：United States  

Event date： 2019.9 - 2020.7

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Venue：Houston, TX.   Country：United States  

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Venue：Orlando, FL.   Country：United States  

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Venue：Aspen, CO.   Country：United States  

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Venue：Aspen, CO.   Country：United States  

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Venue：Aspen, CO.   Country：United States  

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Venue：Aspen, CO.   Country：United States  

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Venue：Aspen, CO.   Country：United States  

Event date： 2019.6

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Venue：大阪   Country：Japan  

Event date： 2019.6

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Venue：大阪   Country：Japan  

Event date： 2018.9 - 2019.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：大阪   Country：Japan  

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Venue：Fukuoka   Country：Japan  

Language：Japanese