記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blood  

Therapy resistance in acute myeloid leukemia (AML) remains a major clinical obstacle, particularly because of the persistence of leukemia stem cells (LSC) capable of metabolic adaptation. Although venetoclax (Ven) inhibits oxidative phosphorylation (OXPHOS), we found that Ven-resistant LSC undergo glycolytic reprogramming to bypass OXPHOS inhibition. This metabolic shift is supported by enhanced ribosome biogenesis, which is sustained by upregulated de novo guanine nucleotide biosynthesis. Abundant guanine nucleotides suppress the impaired ribosome biogenesis checkpoint (IRBC), leading to TP53 destabilization and persistent MYC expression. The inhibition of inosine monophosphate dehydrogenases (IMPDH1/2) depletes guanine nucleotides, activates IRBC, stabilizes TP53, represses MYC, and impairs the metabolic shift to glycolysis. This metabolic rewiring disrupts LSC stemness and suppresses the reconstitution of human AML cells in xenotransplantation experiments. Notably, the suppression of LSC stemness was observed regardless of Ven resistance or the TP53 mutational status of AML cells. These findings reveal that mutation-independent TP53 inactivation is involved in resistant AML and suggest that targeting guanine nucleotide biosynthesis may offer a clinically actionable strategy to eradicate therapy-resistant LSC.

DOI： 10.1182/blood.2025030209

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blood  

Acute myeloid leukemia (AML) with TP53 mutations is almost universally refractory to chemotherapy, molecular-targeted therapies, and hematopoietic stem cell transplantation, leading to dismal clinical outcomes. The lack of effective treatments underscores the urgent need for novel therapeutic strategies. Using genome-wide CRISPR/Cas9 dropout screens in isogenic Trp53–wild-type (WT) and Trp53-knockout mouse AML models, combined with transcriptomic and proteomic analyses of AML samples from mice and humans, we identify the XPO7-NPAT (exportin 7–nuclear protein, coactivator of histone transcription) pathway as essential for TP53-mutated AML cell survival. In TP53-WT AML, XPO7 functions as a tumor suppressor by regulating the nuclear abundance of p53 protein, particularly when basal levels of functional p53 are high. However, in TP53-mutated AML, XPO7 drives leukemia proliferation by retaining NPAT, an XPO7-associated protein predominantly expressed in TP53-mutated AML, within the nucleus. NPAT depletion induces genome-wide histone loss, compromises genomic integrity, and triggers replication catastrophe in TP53-mutated AML cells. Notably, the analysis of publicly available AML data sets, primary AML samples, and single-cell intrapatient mRNA profiles further reveals elevated XPO7 and NPAT expression in TP53-mutated AML. Finally, we validate the XPO7-NPAT pathway as a critical driver of leukemia progression in vivo using patient-derived xenograft models of TP53-WT and TP53-mutant AML. Our study delineates key molecular mechanisms underlying TP53-mutated AML pathogenesis and identifies the XPO7-NPAT axis as a critical vulnerability in this refractory leukemia subtype.

DOI： 10.1182/blood.2025028918

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PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本輸血・細胞治療学会  

<p>キメラ抗原受容体（chimeric antigen receptor：CAR）-T細胞療法において，十分な細胞数の採取が重要である．しかし前治療や原疾患によって末梢血中のリンパ球数が減少していることも多く，処理血液量の過不足が課題である．本研究ではCAR-T製造を目的としてアフェレーシスを実施した108例を対象に，前日の末梢血CD3陽性細胞数および単核球中CD3陽性細胞割合と，アフェレーシス産物のCD3陽性細胞数との関連を解析した．CD3陽性細胞数の逆数を用いた単回帰モデルにより，びまん性大細胞型B細胞リンパ腫に対するTisagenlecleucel製造に必要なCD3陽性細胞数（1.5×10⁹ cells）を得るための適正な処理血液量が予測可能であった．さらに，前日末梢血単核球中CD3陽性細胞割合とアフェレーシス産物のCD3陽性細胞割合との間にも強い相関が認められ，アフェレーシス前日の検査値に基づく実用的な採取戦略の構築が可能となった．本手法はCAR-T療法におけるアフェレーシス計画の個別化と標準化を支援し得る可能性があるが，さらなる検討を要する．</p>

DOI： 10.3925/jjtc.71.799

CiNii Research

記述言語：日本語   出版者・発行元：(一社)日本輸血・細胞治療学会  

キメラ抗原受容体(chimeric antigen receptor:CAR)-T細胞療法において,十分な細胞数の採取が重要である.しかし前治療や原疾患によって末梢血中のリンパ球数が減少していることも多く,処理血液量の過不足が課題である.本研究ではCAR-T製造を目的としてアフェレーシスを実施した108例を対象に,前日の末梢血CD3陽性細胞数および単核球中CD3陽性細胞割合と,アフェレーシス産物のCD3陽性細胞数との関連を解析した.CD3陽性細胞数の逆数を用いた単回帰モデルにより,びまん性大細胞型B細胞リンパ腫に対するTisagenlecleucel製造に必要なCD3陽性細胞数(1.5×10^9 cells)を得るための適正な処理血液量が予測可能であった.さらに,前日末梢血単核球中CD3陽性細胞割合とアフェレーシス産物のCD3陽性細胞割合との間にも強い相関が認められ,アフェレーシス前日の検査値に基づく実用的な採取戦略の構築が可能となった.本手法はCAR-T療法におけるアフェレーシス計画の個別化と標準化を支援し得る可能性があるが,さらなる検討を要する.(著者抄録)

記述言語：英語   出版者・発行元：(一社)日本小児血液・がん学会  

記述言語：英語   出版者・発行元：(一社)日本小児血液・がん学会  

記述言語：英語   出版者・発行元：島根大学医学部  

記述言語：英語   出版者・発行元：(一社)日本血液学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Hematology  

Post-transplant lymphoproliferative disorders (PTLDs) typically arise months to years after solid-organ transplantation and are frequently driven by Epstein–Barr virus (EBV). However, EBV-negative monomorphic PTLDs are increasingly recognized as an alternative pathogenesis. We report a case of a 64-year-old man who underwent liver transplantation and was found to have a minute focus of diffuse large B-cell lymphoma (DLBCL) in the resected gallbladder. Given the absence of residual disease and the patient’s postoperative frailty, close observation was chosen. Three months later, the patient developed an aggressive clinical relapse characterized by Burkitt-like features, including massive effusions and gastric wall thickening. Retrospective analysis using a 398-gene panel (DISCAVar) revealed that both the initial and recurrent lesions shared an IGH::MYC rearrangement, while the recurrent tumor acquired additional Burkitt lymphoma (BL)-associated mutations (TP53, TCF3, CCND3, DDX3X) absent in the original lesion. These alterations spanned all three molecular subgroups of BL and suggest rapid clonal evolution from a pre-existing MYC-positive clone under post-transplant immunosuppression. Despite treatment with dose-modified EPOCH, the patient’s condition deteriorated, and he died 108 days after treatment initiation. This case underscores the value of longitudinal molecular analysis in understanding the pathogenesis of EBV-negative PTLD and identifying high-risk clones before clinical transformation.

DOI： 10.1007/s12185-025-04078-x

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DOI： 10.1182/blood-2025-5116

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DOI： 10.1182/blood-2025-5158

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記述言語：英語  

DOI： 10.1182/blood-2025-7702

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掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society of Hematology  

Abstract

The master transcription factor GATA2 is indispensable for hematopoietic stem cell homeostasis and the integrity of multilineage blood development. Germline heterozygous mutations in GATA2 result in GATA2 haploinsufficiency, leading to GATA2 deficiency syndrome—a complex, pleiotropic disorder characterized by profound immunodeficiency and a high predisposition for progression to MDS and AML. Despite its clinical significance, current limitations in public variant annotation hinder the ability to assess individual GATA2 variants in clinical practice. For example, in the ClinVar database, 89.9% of GATA2 single nucleotide variants (SNVs) are classified as variants of uncertain significance (VUS) or as those with conflicting interpretations (accessed July 31, 2025), underscoring the urgent need for alternative approaches to assess their pathogenicity.

While multiple methods combining CRISPR perturbations with scRNA-seq have been reported, to our knowledge, no existing technology enables the systematic introduction of any desired missense mutation alongside simultaneous assessment of the resulting genotype and transcriptomic changes at single-cell resolution. Here, we developed GenoPrime-Perturb-seq (simultaneous Genotyping-coupled Prime-editing Perturb-seq), a novel platform for high-throughput prime editing integrated with single-cell genotyping and transcriptomic profiling. This approach, for the first time, enables the functional interrogation of individual GATA2 variants at single-cell resolution.

GATA2 is a critical regulator of basophil lineage commitment, and its loss has been shown to skew hematopoietic progenitors toward neutrophil and/or eosinophil lineages. We found that the KU812 line, an immature basophilic leukemia cell line derived from a CML patient, showed upregulation of key granulocytic transcription factors such as CEBPA following GATA2 depletion. To validate the capacity of GenoPrime-Perturb-seq, we first applied it to KU812 cells by introducing either a canonical loss-of-function (R330*) or gain-of-function (L359V) GATA2 variant. We confirmed efficient on-target editing of each variant with high-fidelity and detected transcriptomic changes at single-cell resolution: cells harboring the R330* and L359V mutations segregated into distinct clusters, as expected. For example, the R330*-enriched cluster exhibited a transcriptome similar to that of neutrophil- and/or eosinophil-like lineages, marked by the upregulation of CEBPA and CEBPE.

To assess the functional significance of individual GATA2 VUS within the dual zinc-finger domain, where most reported variants concentrated, we performed GenoPrime-Perturb-seq targeting 149 GATA2 SNVs listed in the ClinVar and MGeND databases. Strikingly, GenoPrime-Perturb-seq demonstrated high classification accuracy, achieving an AUC &amp;gt;0.9 in ROC analysis, with both sensitivity and specificity exceeding 0.9 at the Youden index threshold, when ClinVar-designated pathogenic variants and bootstrapped wild-type data were used as positive and negative labels, respectively. Furthermore, GenoPrime-Perturb-seq showed significantly superior performance in detecting cells differentiating towards the neutrophil- and eosinophil-like lineages compared to a method combining scRNA-seq with prime editing guide RNA capture.

Finally, to validate the results of GenoPrime-Perturb-seq with an orthogonal system, we performed a bulk prime editing screen on 149 variants using an iPSC-to-hematopoietic progenitor cell (HPC) differentiation model, in which GATA2 knockout has been reported to block differentiation toward HPCs. As expected, the majority of the variants classified as pathogenic by GenoPrime-Perturb-seq resulted in impaired HPC formation. However, unexpectedly, some “loss-of-function” variants—defined by the KU812 screen—enhanced HPC development, suggesting that certain GATA2 variants may exert distinct functions in a differentiation stage-specific manner. Notably, these variants exhibited a pronounced block in neutrophil maturation in the KU812 assay and were clustered within the ZF1 domain.

In conclusion, we have developed GenoPrime-Perturb-seq, a novel platform that enables high-throughput, high-fidelity functional assessment of variants. This system successfully evaluated the functional significance of individual GATA2 variants and may help bridge the gap between genomic variation and clinical phenotype, offering a promising approach for resolving a wide range of uncertain variants.

DOI： 10.1182/blood-2025-3215

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記述言語：英語   出版者・発行元：American Society of Hematology  

Acute myeloid leukemia (AML) with TP53 mutations is almost universally refractory to chemotherapy, molecular-targeted therapies, and hematopoietic stem cell transplantation, leading to dismal clinical outcomes. The lack of effective treatments underscores the urgent need for novel therapeutic strategies. Using genome-wide CRISPR/Cas9 dropout screens in isogenic Trp53-wild-type (WT) and knockout (KO) mouse AML models, combined with transcriptomic and proteomic analyses of mouse and human AML samples, we identify the XPO7 (exportin 7)–NPAT (nuclear protein, coactivator of histone transcription) pathway as essential for TP53-mutated AML cell survival. In TP53-WT AML, XPO7 functions as a tumor suppressor by regulating nuclear abundance of p53 protein, particularly when basal levels of functional p53 are high. However, in TP53-mutated AML, XPO7 drives leukemia proliferation by retaining NPAT, an XPO7-associated protein predominantly expressed in TP53-mutated AML, within the nucleus. NPAT depletion induces genome-wide histone loss, compromises genomic integrity, and triggers replication catastrophe in TP53-mutated AML cells. Notably, analysis of publicly available AML datasets, primary AML samples, and single-cell intra-patient mRNA profiles further reveals elevated XPO7 and NPAT expression in TP53-mutated AML. Finally, we validate the XPO7-NPAT pathway as a critical driver of leukemia progression in vivo using patient-derived xenograft (PDX) models of TP53-WT and TP53-mutant AML. Our study delineates key molecular mechanisms underlying TP53-mutated AML pathogenesis and identifies the XPO7-NPAT axis as a critical vulnerability in this refractory leukemia subtype.

CiNii Research

記述言語：英語   出版者・発行元：(一社)日本血液学会  

記述言語：日本語   出版者・発行元：(一社)日本サイトメトリー学会  

記述言語：英語   出版者・発行元：(一社)日本血液学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment landscape for relapsed or refractory non-Hodgkin lymphoma, achieving a 5-year overall survival rate of 40-50%. However, relapse remains a major challenge, especially due to CD19-negative clones. Epcoritamab, a bispecific antibody targeting CD20 and CD3, offers a potential solution for post-CAR-T relapse; however, clinical data in this setting remain limited, particularly in Japan. THE CASE: A 68-year-old woman with CD5-positive diffuse large B-cell lymphoma (DLBCL) relapsed multiple times following various treatments, including CAR-T therapy. Genetic profiling revealed a MYD88/CD79B-mutated (MCD) subtype with CD19-negative clones resistant to CAR-T cells. Given her high tumor burden, she received debulking therapy followed by epcoritamab treatment. Despite concerns about tumor lysis syndrome, cytokine release syndrome, and neurotoxicity, no significant adverse events occurred. The patient achieved a complete remission, demonstrating the efficacy and safety of this approach. CONCLUSION: This case highlights the potential of epcoritamab combined with debulking therapy for treating CAR-T-refractory CD19-negative DLBCL. This is the first validated case in Japan showing that epcoritamab is a viable and safe treatment option for post-CAR-T relapse, addressing a critical unmet need in the current therapeutic landscape.

DOI： 10.31547/bct-2024-037

PubMed

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

高リスク急性骨髄性白血病(AML)に対して同種幹細胞移植を行った後の症例を対象に、白血病幹細胞(LSC)に特異的な機能的表面分子マーカーであるT-cell immunoglobulin mucin-3(TIM-3)が陽性となる頻度を評価し、再発との相関性を解析した。AML患者83名で行われた同種幹細胞移植92件を解析対象とした。その移植で血液学的完全寛解と完全なドナー細胞キメリズムが達成された直後に、CD34陽性CD38陰性の骨髄細胞集団(測定可能な残存LSC;MR-LSC)におけるTIM-3陽性細胞の出現頻度を調べた。その頻度に応じて患者集団を高(同頻度が90%超)、中、低(60%未満)の3群に分類した。その結果、6ヵ月以内のAML再発率はこの順で100%、83.3%、22.2%となった。MR-LSCのTIM-3陽性状態は再発に関する有意な独立危険因子であることも示され(ハザード比8.56、p<0.0001)、それによる影響の強さは、完全寛解達成失敗といった疾患状態の因子を上回っていた。以上の所見から、AML患者への同種幹細胞移植の直後におけるTIM-3陽性MR-LSCの状態は、残存TIM-3陽性LSCとドナーの造血幹細胞が競合した状態で再構築された様相を反映していることが明らかになった。

担当区分：筆頭著者  

Web of Science

記述言語：日本語   出版者・発行元：(一社)日本小児血液・がん学会  

記述言語：英語   出版者・発行元：国立大学法人 島根大学医学部  

<p><i><b>Background:</b></i> Comprehensive Genomic Profiling (CGP) testing has been covered by insurance in Japan since 2019. Miyazaki Prefectural Hospital began CGP in January 2024 after designation as a Cancer Genome Collaboration Hospital in 2023. <i><b>Methods:</b></i> A retrospective study was conducted on 24 CGP cases from January to December 2024 to assess current status and future challenges. <i><b>Results:</b></i> Median patient age was 60 years (range: 39–82), with female predominance (7 males, 17 females). All tests used tissue samples and the FoundationOne® CDx platform. CGP was conducted at first-line in 12% (rare/unknown primary), second-line in 46%, and third-line in 42%. Mean time from CGP submission to expert panel review was 32.1 days. Major tumor types were gastrointestinal (50%) and gynecologic (42%) cancers. DNA analysis was successful in all cases. The median number of actionable alterations was 5 (IQR: 1–9; range: 1–15). Common genomic alterations included <i>TP53</i> and <i>PIK3CA</i> mutations. In addition, high tumor mutational burden (<i>TMB high</i>) was frequently observed as a biomarker feature. All 24 cases harbored at least one actionable mutation. Drug-accessible alterations were found in 62% (15/24), and 29% (7/24) received targeted treatments (treatment-matched rate), including pembrolizumab and capivasertib. Implementation rates varied by tumor type: 60% in gallbladder, 14% in uterine, and 33% in intrahepatic cholangiocarcinoma. Targeted therapy showed a trend toward prolonged survival without statistical significance. One case required genetic counseling for <i>STK11</i> mutation. <i><b>Conclusion:</b></i> CGP has expanded opportunities to explore novel treatment strategies based on genomic alterations. It proved feasible and clinically valuable for identifying actionable mutations and guiding therapy. Future efforts should optimize timing, broaden access, and enhance data to advance precision oncology.</p>

DOI： 10.51010/sjms.42.3-4_47

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

In this study, we investigated the measurable residual leukemic stem cell (MR-LSC) population after allogeneic stem cell transplantation (allo-SCT) for high-risk acute myeloid leukemia (AML), utilizing T-cell immunoglobulin mucin-3 (TIM-3) expression as a functional marker of AML leukemic stem cells (LSCs). Analysis of the CD34⁺CD38⁻ fraction of bone marrow cells immediately after achievement of engraftment revealed the presence of both TIM-3⁺LSCs and TIM-3⁻ donor hematopoietic stem cells (HSCs) at varying ratios. Genetic analysis confirmed that TIM-3⁺ cells harbored patient-specific mutations identical to those found in AML clones, whereas TIM-3⁻ cells did not, indicating that TIM-3⁺CD34⁺CD38⁻ cells represent residual AML LSCs. In 92 allo-SCT occasions involving 83 AML patients, we enumerated the frequencies of TIM-3⁺LSCs immediately after achieving hematologic complete remission with complete donor cell chimerism. Notably, only 22.2% of patients who achieved a TIM-3⁺MR-LSC^low status (<60%) experienced relapse, with a median event-free survival (EFS) of 1581 days (median follow-up duration was 2177 days among event-free survivors). Conversely, 87.5% of patients with TIM-3⁺MR-LSC^int/high (≥60%) relapsed, with a median EFS of 140.5 days. Furthermore, MR-LSC status emerged as a significant independent risk factor for relapse (hazard ratio, 8.56; p < 0.0001), surpassing the impact of patient disease status prior to allo-SCT, including failure to achieve complete remission (hazard ratio, 1.98; p = 0.048). These findings suggest that evaluating TIM-3⁺ MR-LSCs immediately after engraftment, which reflects the competitive reconstitution of residual TIM-3⁺ LSCs and donor HSCs, may be valuable for predicting outcomes in AML patients undergoing allo-SCT.

DOI： 10.1111/cas.16431

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DOI： 10.1182/blood-2024-199401

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記述言語：英語  

DOI： 10.1182/blood-2024-206451

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

According to the 2016 World Health Organization classification, a germline DEAD-box helicase 41 gene (DDX41) mutation with myeloid neoplasms has been newly classified. The clinical course of acute myeloid leukemia (AML) with a germline DDX41 mutation has not yet been clarified. In the early phase, this condition is slowly progressive, the rate of remission induction is high, and the prognosis is good. On the other hand, in the late phase, the gradual relapse rate increases and the ultimate prognosis can be poor. Currently, clear guidance on the indication for allogeneic hematopoietic stem cell transplantation (allogeneic HSCT) for AML with a germline DDX41 mutation has not been yet provided. However, we consider that allogeneic HSCT should be performed in patients who are eligible for allogeneic HSCT for germline DDX41 mutations in AML to overcome poor relapse-free survival, referring to previous relevant papers. We report a 49-year-old patient who had pancytopenia and was finally diagnosed with a germline DDX41 mutation and AML. We decided to perform allogeneic HSCT. On day 68, he was complicated by acute graft versus host disease, gut stage 1, grade II, and was started on prednisolone 0.2 mg/kg. He recovered quickly and has been currently alive without symptoms of graft versus host disease for almost 2 years. Regarding donor search for allogeneic HSCT for AML with a germline DDX41 mutation, it is essential to ensure that the donor must be negative for this mutation when the donor is a family donor. If the related donor has a positive mutation, which can cause the development of donor-derived leukemia, allogeneic HSCT should performed from an unrelated donor.

DOI： 10.1155/2024/4611649

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Leukemia  

Selinexor, a first-in-class exportin1 (XPO1) inhibitor, is an attractive anti-tumor agent because of its unique mechanisms of action; however, its dose-dependent toxicity and lack of biomarkers preclude its wide use in clinical applications. To identify key molecules/pathways regulating selinexor sensitivity, we performed genome-wide CRISPR/Cas9 dropout screens using two B-ALL lines. We identified, for the first time, that paralogous DDX19A and DDX19B RNA helicases modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export. While single depletion of either DDX19A or DDX19B barely altered MCL1 protein levels, depletion of both significantly attenuated MCL1 mRNA nuclear export, reducing MCL1 protein levels. Importantly, combining selinexor treatment with depletion of either DDX19A or DDX19B markedly induced intrinsic apoptosis of leukemia cells, an effect rescued by MCL1 overexpression. Analysis of Depmap datasets indicated that a subset of T-ALL lines expresses minimal DDX19B mRNA levels. Moreover, we found that either selinexor treatment or DDX19A depletion effectively induced apoptosis of T-ALL lines expressing low DDX19B levels. We conclude that XPO1 and DDX19A/B coordinately regulate cellular MCL1 levels and propose that DDX19A/B could serve as biomarkers for selinexor treatment. Moreover, pharmacological targeting of DDX19 paralogs may represent a potential strategy to induce intrinsic apoptosis in leukemia cells.

DOI： 10.1038/s41375-024-02343-2

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CiNii Research

記述言語：英語   出版者・発行元：Pediatric Blood and Cancer  

DOI： 10.1002/pbc.31119

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blood Neoplasia  

Glucocorticoids (GCs), such as dexamethasone and prednisone, are crucial components of B-cell precursor acute lymphoblastic leukemia (B-ALL) therapies. However, the molecular basis of GC-induced cell death remains elusive. Here, we show that GC suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling and that, conversely, oncogenic activation of mTORC1 confers resistance to GCs. Our genome-wide CRISPR/CRISPR-associated protein 9 (CRISPR/Cas9) dropout screens reveal that depletion of components of either the gap activity toward Rags 1 or tuberous sclerosis complexes, both negative regulators of mTORC1 signaling, significantly attenuates B-ALL cell sensitivity to dexamethasone. Dexamethasone primarily induces B-ALL cell death by downregulating mTORC1 activity, thus promoting autophagy and impairing protein synthesis. Dexamethasone treatment failed to suppress mTORC1 activity in B-ALL cells expressing mutant GC receptors lacking DNA-binding capacity, suggesting that dexamethasone transcriptionally represses mTORC1 activity. RNA-sequencing analysis identified multiple dexamethasone target genes that negatively regulate mTORC1 activity. Our findings suggest that GC sensitivity is significantly influenced by oncogenic stimuli and/or growth factors that activate the PI3K-AKT-mTORC1 pathway. This is consistent with the frequent GC resistance found in Ph and Ph-like ALLs.

DOI： 10.1016/j.bneo.2024.100015

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PubMed

記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

27歳女性。汎血球減少を認め入院,骨髄検査でmyeloperoxidase陽性芽球を52.2%認め急性骨髄性白血病と診断した。白血病キメラスクリーニング検査でCBFB::MYH11を含むキメラ遺伝子は検出されなかったがG-band法による染色体分析でinv(16)(p13.1q22)を認め,fluorescence in situ hybridization(FISH)検査でCBFBのsplit signalを認めた。PCRプライマーを変更しキメラスクリーニングの再検討を行いCBFB::MYH11が検出された。RNA-sequencingによる融合遺伝子検索にて稀なtype I CBFB::MYH11が同定された。本症例はキメラスクリーニングで陰性になりうるCBFB::MYH11の一亜型が存在することを示し,その検索にPCRプライマーの変更やFISH検査,RNA-sequencingが有用であることを示す貴重な症例である。(著者抄録)

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3324/haematol.2023.283163

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PubMed

記述言語：英語  

DOI： 10.1182/blood-2023-182620

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DOI： 10.1182/blood-2023-188986

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

記述言語：英語   出版者・発行元：(一社)日本血液学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Communications Biology  

Protection of telomeres 1a (POT1a) is a telomere binding protein. A decrease of POT1a is related to myeloid-skewed haematopoiesis with ageing, suggesting that protection of telomeres is essential to sustain multi-potency. Since mesenchymal stem cells (MSCs) are a constituent of the hematopoietic niche in bone marrow, their dysfunction is associated with haematopoietic failure. However, the importance of telomere protection in MSCs has yet to be elucidated. Here, we show that genetic deletion of POT1a in MSCs leads to intracellular accumulation of fatty acids and excessive ROS and DNA damage, resulting in impaired osteogenic-differentiation. Furthermore, MSC-specific POT1a deficient mice exhibited skeletal retardation due to reduction of IL-7 producing bone lining osteoblasts. Single-cell gene expression profiling of bone marrow from POT1a deficient mice revealed that B-lymphopoiesis was selectively impaired. These results demonstrate that bone marrow microenvironments composed of POT1a deficient MSCs fail to support B-lymphopoiesis, which may underpin age-related myeloid-bias in haematopoiesis.

DOI： 10.1038/s42003-023-05374-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Classic Hodgkin lymphoma (CHL) harbors a small number of Hodgkin-Reed-Sternberg (HRS) cells scattered among numerous lymphocytes. HRS cells are surrounded by distinct CD4⁺ T cells in a rosette-like manner. These CD4⁺ T cell rosettes play an important role in the tumor microenvironment (TME) of CHL. To elucidate the interaction between HRS cells and CD4⁺ T cell rosettes, we completed digital spatial profiling to compare the gene expression profiles of CD4⁺ T cell rosettes and other CD4⁺ T cells separated from the HRS cells. Immune checkpoint molecules including OX40, programed cell death-1 (PD-1), and cytotoxic T lymphocyte associated protein 4 (CTLA-4) expression was higher in CD4⁺ T cell rosettes compared to other CD4⁺ T cells. Immunohistochemistry confirmed variable PD-1, CTLA-4, and OX40 expression in the CD4⁺ T cell rosettes. This study introduced a new pathological approach to study the CHL TME, and provided deeper insight into CD4⁺ T cells in CHL.

DOI： 10.1007/s00428-023-03562-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blood Advances  

Cancer-specific metabolic activities play a crucial role in the pathogenesis of human malignancies. To investigate human acute leukemia–specific metabolic properties, we comprehensively measured the cellular metabolites within the CD34+ fraction of normal hematopoietic stem progenitor cells (HSPCs), primary human acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) cells. Here, we show that human leukemia cells are addicted to the branched-chain amino acid (BCAA) metabolism to maintain their stemness, irrespective of myeloid or lymphoid types. Human primary acute leukemias had BCAA transporters for BCAA uptake, cellular BCAA, α-ketoglutarate (α-KG), and cytoplasmic BCAA transaminase-1 (BCAT1) at significantly higher levels than control HSPCs. Isotope-tracing experiments showed that in primary leukemia cells, BCAT1 actively catabolizes BCAA using α-KG into branched-chain α-ketoacids, whose metabolic processes provide leukemia cells with critical substrates for the trichloroacetic acid cycle and the synthesis of nonessential amino acids, both of which reproduce α-KG to maintain its cellular level. In xenogeneic transplantation experiments, deprivation of BCAA from daily diet strongly inhibited expansion, engraftment and self-renewal of human acute leukemia cells. Inhibition of BCAA catabolism in primary AML or ALL cells specifically inactivates the function of the polycomb repressive complex 2, an epigenetic regulator for stem cell signatures, by inhibiting the transcription of PRC components, such as zeste homolog 2 and embryonic ectoderm development. Accordingly, BCAA catabolism plays an important role in the maintenance of stemness in primary human AML and ALL, and molecules related to the BCAA metabolism pathway should be critical targets for acute leukemia treatment.

DOI： 10.1182/bloodadvances.2022008242

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature  

Sex chromosome disorders severely compromise gametogenesis in both males and females. In oogenesis, the presence of an additional Y chromosome or the loss of an X chromosome disturbs the robust production of oocytes1–5. Here we efficiently converted the XY chromosome set to XX without an additional Y chromosome in mouse pluripotent stem (PS) cells. In addition, this chromosomal alteration successfully eradicated trisomy 16, a model of Down’s syndrome, in PS cells. Artificially produced euploid XX PS cells differentiated into mature oocytes in culture with similar efficiency to native XX PS cells. Using this method, we differentiated induced pluripotent stem cells from the tail of a sexually mature male mouse into fully potent oocytes, which gave rise to offspring after fertilization. This study provides insights that could ameliorate infertility caused by sex chromosome or autosomal disorders, and opens the possibility of bipaternal reproduction.

DOI： 10.1038/s41586-023-05834-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Pediatric Blood and Cancer  

DOI： 10.1002/pbc.29915

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Hematology  

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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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本血液学会  

<p>27歳女性。汎血球減少を認め入院，骨髄検査でmyeloperoxidase陽性芽球を52.2％認め急性骨髄性白血病と診断した。白血病キメラスクリーニング検査で<i>CBFB::MYH11</i>を含むキメラ遺伝子は検出されなかったがG-band法による染色体分析でinv（16）（p13.1q22）を認め，fluorescence <i>in situ</i> hybridization（FISH）検査で<i>CBFB</i>のsplit signalを認めた。PCRプライマーを変更しキメラスクリーニングの再検討を行い<i>CBFB::MYH11</i>が検出された。RNA-sequencingによる融合遺伝子検索にて稀なtype I <i>CBFB::MYH11</i>が同定された。本症例はキメラスクリーニングで陰性になりうる<i>CBFB::MYH11</i>の一亜型が存在することを示し，その検索にPCRプライマーの変更やFISH検査，RNA-sequencingが有用であることを示す貴重な症例である。</p>

DOI： 10.11406/rinketsu.64.1503

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語  

DOI： 10.1182/blood-2022-164647

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DOI： 10.1182/blood-2022-168650

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記述言語：英語   出版者・発行元：(一社)日本小児血液・がん学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Gastric Cancer  

Background: 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. Methods: 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). Results: 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. Conclusions: 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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記述言語：英語   出版者・発行元：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。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：(一社)日本サイトメトリー学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Letters  

Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45+CD14+ CAMs transdifferentiated into CD45−CD90+ fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45−CD90+ fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFβ signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFβ and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.

DOI： 10.1016/j.canlet.2022.215597

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Immunology  

T follicular regulatory (Tfr) cells are a subset of CD4+ T cells that express CXCR5 and migrate into germinal centers (GCs). They regulate GC reactions by communicating with T follicular helper (Tfh) and B cells. TNF inhibitors are used in inflammatory diseases; however, the generation of autoantibodies or anti-drug Abs sometimes causes problems. Because TNFR2 signaling is important for suppressive functions of regulatory T cells, we investigated the role of TNFR2 on human Tfr cells. Tfr cells stimulated with MR2-1 (an anti-TNFR2 agonistic Ab) were analyzed for cell proliferation, Foxp3 expression, and surface molecules. Tfh/B cell proliferation, IgM production, and differentiation in cocultures with MR2-1-stimulated Tfr cells were examined. Tfr cells express a high level of TNFR2. MR2-1 stimulation altered the gene expression profile of Tfr cells. Cell proliferation and Foxp3 expression of Tfr cells were enhanced by MR2-1. MR2-1-stimulated Tfr cells expressed ICOS and Programmed cell death protein 1 and significantly suppressed Tfh/B cell proliferation, IgM production, and B cell differentiation. TNFR2-stimulated Tfr cells retained the migration function according to the CXCL13 gradient. In conclusion, we showed that TNFR2-stiumulated Tfr cells can regulate Tfh and B cells. Aberrant antibody production during TNF inhibitor treatment might be, at least in part, associated with TNFR2 signaling inhibition in Tfr cells. In addition, expansion and maturation of Tfr cells via TNFR2 stimulation in vitro may be useful for a cell-based therapy in inflammatory and autoimmune diseases to control GC reactions.

DOI： 10.4049/jimmunol.2100323

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Leukemia  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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