論文 - 籠谷　勇紀

Plasma membrane-coated nanoparticles and membrane vesicles to orchestrate multimodal antitumor immunity

Ito Y., Kasuya H., Kataoka M., Nakamura N., Yoshikawa T., Nakashima T., Zhang H., Li Y., Matsukawa T., Inoue S., Oneyama C., Ohta S., Kagoya Y.

Journal for ImmunoTherapy of Cancer 13 （ 1 ）  2025年01月

最終著者, 責任著者, 査読有り

　概要を見る

Background A number of immunotherapeutic approaches have been developed and are entering the clinic. Bispecific antibodies (BsAbs) are one of these modalities and induce robust efficacy by endogenous T cells in several hematological malignancies. However, most of the treated patients experience only a temporary benefit. Currently available BsAbs provide only anti-CD3 antibody-mediated T-cell stimulation, but not the costimulation or cytokine signaling essential for full T-cell activation. Here, we hypothesized that the simultaneous input of more comprehensive signals would elicit more robust and durable effector T-cell functions. Methods We genetically engineered the leukemia cell line K562 to express BsAbs, costimulatory ligands, cytokines, and blocking antibodies against immune checkpoint molecules on the cell surface, from which we obtained plasma membrane fractions by mechanical homogenization and subsequent isolation steps. Plasma membranes were reconstituted on the poly (lactic-co-glycolic acid) surface to generate membrane-coated nanoparticles (NPs). Alternatively, nano-sized membrane vesicles (MVs) were generated by ultrasonic dispersion of the isolated membranes. The antitumor function of NPs and MVs loaded with various immunomodulatory factors was evaluated in vitro and in vivo. Results Both membrane-coated NPs and MVs induced BsAb-mediated antigen-specific cytotoxic activity in non-specific T cells, with MVs inducing a slightly better response in vivo. Importantly, T-cell activation was elicited only in the presence of target tumor cells, providing a safety advantage for clinical use. NPs and MVs expressing costimulatory molecules (CD80/4-1BBL) and cytokines (interleukin (IL)-7/IL-15) further enhanced effector T-cell function and induced therapeutic efficacy in vivo. In addition, MVs expressing immune checkpoint antibodies and inflammatory cytokines IL-12 and IL-18 induced objective antitumor responses in solid tumor models partly by converting immunosuppressive macrophages to proinflammatory phenotypes and inducing cytotoxic T-cell infiltration into the tumor. Finally, we showed that MVs were also engineered to activate natural killer (NK) cells by loading multiple ligands. MVs loaded with BsAbs, 4-1BBL, IL-15, and IL-21 induced NK-cell cytotoxic activity in an antigen-specific manner. Conclusions We developed antitumor NPs and MVs that efficiently induced antitumor immune responses in vivo by simultaneously delivering multiple immunostimulatory signals to endogenous T cells. This platform enables the delivery of desired combinations of antitumor immune signals into T cells and NK cells.

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Protocol to measure human IL-6 secretion from CAR T cell-primed macrophage and monocyte lineage cells in vitro and in vivo using humanized mice

Nguyen T., Yoshikawa T., Ito Y., Kasuya H., Nakashima T., Okamoto S., Amaishi Y., Zhang H., Li Y., Matsukawa T., Inoue S., Kagoya Y.

STAR Protocols 5 （ 4 ） 103423 - 103423 2024年12月

最終著者, 責任著者, 査読有り

　概要を見る

Chimeric antigen receptor (CAR) T cell therapy often causes serious toxicities, such as cytokine release syndrome (CRS), mainly due to interleukin-6 (IL-6) secreted by monocyte lineage cells. Here, we describe a protocol to generate anti-CD19 CAR T cells and quantify human monocyte-derived IL-6 cocultured with CAR T cells and target tumor cells in vitro. We further describe a protocol to generate a humanized mouse model and evaluate CAR T cell-associated plasma IL-6 levels in vivo. For complete details on the use and execution of this protocol, please refer to Yoshikawa et al.1

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Gene editing technology to improve antitumor T-cell functions in adoptive immunotherapy

Ito Y., Inoue S., Kagoya Y.

Inflammation and Regeneration （Inflammation and Regeneration）  44 （ 1 ）  2024年12月

最終著者, 責任著者, 査読有り

　概要を見る

Adoptive immunotherapy, in which tumor-reactive T cells are prepared in vitro for adoptive transfer to the patient, can induce an objective clinical response in specific types of cancer. In particular, chimeric antigen receptor (CAR)-redirected T-cell therapy has shown robust responses in hematologic malignancies. However, its efficacy against most of the other tumors is still insufficient, which remains an unmet medical need. Accumulating evidence suggests that modifying specific genes can enhance antitumor T-cell properties. Epigenetic factors have been particularly implicated in the remodeling of T-cell functions, including changes to dysfunctional states such as terminal differentiation and exhaustion. Genetic ablation of key epigenetic molecules prevents the dysfunctional reprogramming of T cells and preserves their functional properties. Clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)-based gene editing is a valuable tool to enable efficient and specific gene editing in cultured T cells. A number of studies have already identified promising targets to improve the therapeutic efficacy of CAR-T cells using genome-wide or focused CRISPR screening. In this review, we will present recent representative findings on molecular insights into T-cell dysfunction and how genetic modification contributes to overcoming it. We will also discuss several technical advances to achieve efficient gene modification using the CRISPR and other novel platforms.

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Current progress of CAR-T-cell therapy for patients with multiple myeloma

Nakashima T, Kagoya Y

Int J Hematol 120 （ 1 ） 15 - 22 2024年05月

最終著者, 責任著者, 査読有り,  ISSN  09255710

　概要を見る

Currently available chimeric antigen receptor (CAR)-engineered T-cell therapies targeting B-cell maturation antigen (BCMA), namely, idecabtagene vicleucel and ciltacabtagene autoleucel, have shown marked efficacy against relapsed and refractory multiple myeloma. However, further improvement in CAR-T-cell function is warranted as most patients treated with these products eventually relapse due to various mechanisms such as antigen loss and T-cell dysfunction or disappearance. Strategies for improving CAR-T-cell function include targeting of dual antigens, enhancing cell longevity through genetic modification, and eliminating the immunosuppressive tumor microenvironment. Serious side effects can also occur after CAR-T-cell infusions. Although understanding of the molecular pathogenesis of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome is growing, the unique movement disorder caused by BCMA-targeted therapy is less understood, and its molecular mechanisms must be further elucidated to establish better management strategies. In this article, we will review the current status of BCMA-targeting CAR-T-cell therapy. We will also highlight progress in the development of CAR-T cells targeting other antigens, as well as universal allogeneic CAR-T cells and bispecific antibodies.

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Development of a chimeric cytokine receptor that captures IL-6 and enhances the antitumor response of CAR-T cells

Toshiaki Yoshikawa, Yusuke Ito, Zhiwen Wu, Hitomi Kasuya, Takahiro Nakashima, Sachiko Okamoto, Yasunori Amaishi, Haosong Zhang, Yang Li, Tetsuya Matsukawa, Satoshi Inoue, Yuki Kagoya

Cell Reports Medicine （Elsevier BV）  5 （ 5 ） 101526 - 101526 2024年05月

最終著者, 責任著者, 査読有り,  ISSN  2666-3791

　概要を見る

The efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy is suboptimal in most cancers, necessitating further improvement in their therapeutic actions. However, enhancing antitumor T cell response inevitably confers an increased risk of cytokine release syndrome associated with monocyte-derived interleukin-6 (IL-6). Thus, an approach to simultaneously enhance therapeutic efficacy and safety is warranted. Here, we develop a chimeric cytokine receptor composed of the extracellular domains of GP130 and IL6RA linked to the transmembrane and cytoplasmic domain of IL-7R mutant that constitutively activates the JAK-STAT pathway (G6/7R or G6/7R-M452L). CAR-T cells with G6/7R efficiently absorb and degrade monocyte-derived IL-6 in vitro. The G6/7R-expressing CAR-T cells show superior expansion and persistence in vivo, resulting in durable antitumor response in both liquid and solid tumor mouse models. Our strategy can be widely applicable to CAR-T cell therapy to enhance its efficacy and safety, irrespective of the target antigen.

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High CD62L expression predicts the generation of chimeric antigen receptor T cells with potent effector functions

Hitomi Kasuya, Haosong Zhang, Yusuke Ito, Toshiaki Yoshikawa, Takahiro Nakashima, Yang Li, Tetsuya Matsukawa, Satoshi Inoue, Yuki Kagoya

International Immunology （Oxford University Press (OUP)）  36 （ 7 ） 353 - 364 2024年03月

最終著者, 責任著者, 査読有り,  ISSN  09538178

　概要を見る

The efficient generation of chimeric antigen receptor (CAR) T cells is highly influenced by the quality of apheresed T cells. Healthy donor-derived T cells usually proliferate better than patients-derived T cells and are precious resources to generate off-the-shelf CAR-T cells. However, relatively little is known about the determinants that affect the efficient generation of CAR-T cells from healthy donor-derived peripheral blood mononuclear cells (PBMCs) compared with those from the patients’ own PBMCs. We here examined the efficiency of CAR-T cell generation from multiple healthy donor samples and analyzed its association with the phenotypic features of the starting peripheral blood T cells. We found that CD62L expression levels within CD8+ T cells were significantly correlated with CAR-T cell expansion. Moreover, high CD62L expression within naïve T cells was associated with the efficient expansion of T cells with a stem cell-like memory phenotype, an indicator of high-quality infusion products. Intriguingly, genetic disruption of CD62L significantly impaired CAR-T cell proliferation and cytokine production upon antigen stimulation. Conversely, ectopic expression of a shedding-resistant CD62L mutant augmented CAR-T cell effector functions compared to unmodified CAR-T cells, resulting in improved antitumor activity in vivo. Collectively, we identified the surface expression of CD62L as a concise indicator of potent T-cell proliferation. CD62L expression is also associated with the functional properties of CAR-T cells. These findings are potentially applicable to selecting optimal donors to massively generate CAR-T cell products.

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Cytokine signaling in chimeric antigen receptor T-cell therapy

Kagoya Y.

International Immunology （International Immunology）  36 （ 2 ） 49 - 56 2024年02月

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  09538178

　概要を見る

Adoptive immunotherapy using chimeric antigen-receptor (CAR)-engineered T cells can induce robust antitumor responses against hematologic malignancies. However, its efficacy is not durable in the majority of the patients, warranting further improvement of T-cell functions. Cytokine signaling is one of the key cascades regulating T-cell survival and effector functions. In addition to cytokines that use the common γchain as a receptor subunit, multiple cytokines regulate T-cell functions directly or indirectly. Modulating cytokine signaling in CAR-T cells by genetic engineering is one promising strategy to augment their therapeutic efficacy. These strategies include ectopic expression of cytokines, cytokine receptors, and synthetic molecules that mimic endogenous cytokine signaling. Alternatively, autocrine IL-2 signaling can be augmented through reprogramming of CAR-T cell properties through transcriptional and epigenetic modification. On the other hand, cytokine production by CAR-T cells triggers systemic inflammatory responses, which mainly manifest as adverse events such as cytokine-release syndrome (CRS) and neurotoxicity. In addition to inhibiting direct inflammatory mediators such as IL-6 and IL-1 released from activated macrophages, suppression of T-cell-derived cytokines associated with the priming of macrophages can be accomplished through genetic modification of CAR-T cells. In this review, I will outline recently developed synthetic biology approaches to exploit cytokine signaling to enhance CAR-T cell functions. I will also discuss therapeutic target molecules to prevent or alleviate CAR-T cell-related toxicities.

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Introduction: Synthetic Biology for Cancer Immunology Special Issue

Kagoya Y.

International Immunology （International Immunology）  36 （ 2 ） 45 - 48 2024年02月

最終著者, 責任著者, 査読有り,  ISSN  09538178

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AKT2 inhibition accelerates the acquisition of phagocytic ability in induced pluripotent stem cell–derived neutrophils

Hino T., Nakahara F., Miyauchi M., Ito Y., Masamoto Y., Morita K., Kagoya Y., Kojima H., Kurokawa M.

Experimental Hematology （Experimental Hematology）  130   104137 - 104137 2024年02月

最終著者, 責任著者, 査読有り,  ISSN  0301472X

　概要を見る

Neutrophils are key components of the immune system that inhibit bacterial infections. Systemic bacterial infections can cause lethal conditions, especially in patients with neutropenia associated with chemotherapy or other systemic illnesses; hence, early detection of the symptoms and prompt management are crucial in such cases. Previously, we established expandable engineered neutrophil-primed progenitors (NeuPs-XL) using human-induced pluripotent stem cells (iPSCs), which can produce neutrophil-like cells at a clinically suitable scale within 4 days of inducing myeloid differentiation. In this study, using small-molecule compound-based screening, we detected that MK-2206, a selective pan-AKT inhibitor, can accelerate this differentiation process, promote phagocytic ability in neutrophils, and enhance cytokine and chemokine expression in response to lipopolysaccharides. The inhibition of AKT2has been identified as the key mechanism underlying this acceleration. These results can make a substantial contribution to the development of strategies for the prompt production of clinically applicable iPSC-derived neutrophils, which can potentially lead to the management of severe infections associated with life-threatening neutropenia and the effective treatment of related health conditions in the future.

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Epigenetic profiles guide improved CRISPR/Cas9-mediated gene knockout in human T cells

Ito Y., Inoue S., Nakashima T., Zhang H., Li Y., Kasuya H., Matsukawa T., Wu Z., Yoshikawa T., Kataoka M., Ishikawa T., Kagoya Y.

Nucleic Acids Research （Nucleic Acids Research）  52 （ 1 ） 141 - 153 2024年01月

最終著者, 責任著者, 査読有り,  ISSN  0305-1048

　概要を見る

Genetic modification of specific genes is emerging as a useful tool to enhance the functions of antitumor T cells in adoptive immunotherapy. Current advances in CRISPR/Cas9 technology enable gene knockout during in vitro preparation of infused T-cell products through transient transfection of a Cas9-guide RNA (gRNA) ribonucleoprotein complex. However, selecting optimal gRNAs remains a major challenge for efficient gene ablation. Although multiple in silico tools to predict the targeting efficiency have been developed, their performance has not been validated in cultured human T cells. Here, we explored a strategy to select optimal gRNAs using our pooled data on CRISPR/Cas9-mediated gene knockout in human T cells. The currently available prediction tools alone were insufficient to accurately predict the indel percentage in T cells. We used data on the epigenetic profiles of cultured T cells obtained from transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). Combining the epigenetic information with sequence-based prediction tools significantly improved the gene-editing efficiency. We further demonstrate that epigenetically closed regions can be targeted by designing two gRNAs in adjacent regions. Finally, we demonstrate that the gene-editing efficiency of unstimulated T cells can be enhanced through pretreatment with IL-7. These findings enable more efficient gene editing in human T cells.

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CD83 expression characterizes precursor exhausted T cell population

Wu Z., Yoshikawa T., Inoue S., Ito Y., Kasuya H., Nakashima T., Zhang H., Kotaka S., Hosoda W., Suzuki S., Kagoya Y.

Communications Biology （Communications Biology）  6 （ 1 ） 258 2023年03月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り

　概要を見る

T cell exhaustion is a main obstacle against effective cancer immunotherapy. Exhausted T cells include a subpopulation that maintains proliferative capacity, referred to as precursor exhausted T cells (TPEX). While functionally distinct and important for antitumor immunity, TPEX possess some overlapping phenotypic features with the other T-cell subsets within the heterogeneous tumor-infiltrating T-lymphocytes (TIL). Here we explore surface marker profiles unique to TPEX using the tumor models treated by chimeric antigen receptor (CAR)-engineered T cells. We find that CD83 is predominantly expressed in the CCR7+PD1+ intratumoral CAR-T cells compared with the CCR7-PD1+ (terminally differentiated) and CAR-negative (bystander) T cells. The CD83+CCR7+ CAR-T cells exhibit superior antigen-induced proliferation and IL-2 production compared with the CD83- T cells. Moreover, we confirm selective expression of CD83 in the CCR7+PD1+ T-cell population in primary TIL samples. Our findings identify CD83 as a marker to discriminate TPEX from terminally exhausted and bystander TIL.

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Dissecting the heterogeneity of exhausted T cells at the molecular level

Kagoya Y.

International Immunology （International Immunology）  34 （ 11 ） 547 - 553 2022年10月

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  09538178

　概要を見る

Our understanding of mechanisms underlying T-cell exhaustion has been refined by analysis of exhausted T cells at the molecular level. The development and functions of exhausted T cells are regulated by a number of transcription factors, epigenetic factors and metabolic enzymes. In addition, recent work to dissect exhausted T cells at the single-cell level has enabled us to discover a precursor exhausted T-cell subset equipped with long-term survival capacity. Starting from the analysis of mouse models, the existence of precursor exhausted T cells has also been documented in human T cells in the context of chronic virus infections or tumors. Clinical data suggest that evaluating the quality of exhausted T cells on the basis of their differentiation status may be helpful to predict the therapeutic response to inhibition of programmed death 1 (PD1). Moreover, beyond immune-checkpoint blockade, novel therapeutic approaches to re-invigorate exhausted T cells have been explored based on molecular insights into T-cell exhaustion. Here I will discuss key molecular profiles associated with the development, maintenance and differentiation of exhausted T cells and how these findings can be applicable in the field of cancer immunotherapy.

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Epigenetic engineering for optimal chimeric antigen receptor T cell therapy

Ito Y., Kagoya Y.

Cancer Science （Cancer Science）  113 （ 11 ） 3664 - 3671 2022年08月

最終著者, 責任著者, 査読有り,  ISSN  13479032

　概要を見る

Recent advancements in cancer immunotherapy, such as chimeric antigen receptor (CAR)-engineered T cell therapy and immune checkpoint therapy, have significantly improved the clinical outcomes of patients with several types of cancer. To broaden its applicability further and induce durable therapeutic efficacy, it is imperative to understand how antitumor T cells elicit cytotoxic functions, survive as memory T cells, or are impaired in their effector functions (exhausted) at the molecular level. T cell properties are regulated by their gene expression profiles, which are further controlled by epigenetic architectures, such as DNA methylation and histone modifications. Multiple studies have elucidated specific epigenetic genes associated with T-cell phenotypic changes. Conversely, exogenous modification of these key epigenetic factors can significantly alter T cell functions by extensively altering the transcription network, which can be applied in cancer immunotherapy by improving T cell persistence or augmenting effector functions. As CAR-T cell therapy involves a genetic engineering step during the preparation of the infusion products, it would be a feasible strategy to additionally modulate specific epigenetic genes in CAR-T cells to improve their quality. Here, we review recent studies investigating how individual epigenetic factors play a crucial role in T-cell biology. We further discuss future directions to integrate these findings for optimal cancer immunotherapy.

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Molecular Profiles of Exhausted T Cells and Their Impact on Response to Immune Checkpoint Blockade

Kagoya Y.

Gan to kagaku ryoho. Cancer & chemotherapy （Gan to kagaku ryoho. Cancer & chemotherapy）  49 （ 6 ） 609 - 614 2022年06月

最終著者, 責任著者, 査読有り,  ISSN  03850684

　概要を見る

T cell exhaustion is induced in the context of chronic virus infection and tumor microenvironment, in which cytotoxic T cells are repeatedly exposed to the target antigen and deprived of their effector functions. Multiple studies have already shown the significant impact of immune checkpoint molecules such as PD1 on functional properties of exhausted T cells. In addition to these signals, exhausted T cells possess distinct transcriptional and epigenetic profiles compared with conventional effector and memory T cells. Importantly, most of these features are not affected by immune checkpoint blockade, suggesting that genetic and epigenetic remodeling of T cells is an underlying molecular mechanism essential for T cell exhaustion. Moreover, it has now been evident that exhausted T cells are a heterogeneous cell population composed of distinct T cell subsets, and these functional differences profoundly affect therapeutic efficacy of cancer immunotherapy. In this review, I will discuss recent studies investigating molecular mechanisms of T cell exhaustion, including novel key molecules essentially associated with T cell exhaustion. These findings are potentially applicable to reinvigorate effector functions of exhausted T cells.

Genetic ablation of PRDM1 in antitumor T cells enhances therapeutic efficacy of adoptive immunotherapy

Yoshikawa T., Wu Z., Inoue S., Kasuya H., Matsushita H., Takahashi Y., Kuroda H., Hosoda W., Suzuki S., Kagoya Y.

Blood （Blood）  139 （ 14 ） 2156 - 2172 2022年04月

最終著者, 責任著者, 査読有り,  ISSN  0006-4971

　概要を見る

Adoptive cancer immunotherapy can induce objective clinical efficacy in patients with advanced cancer; however, a sustained response is achieved in a minority of cases. The persistence of infused T cells is an essential determinant of a durable therapeutic response. Antitumor T cells undergo a genome-wide remodeling of the epigenetic architecture upon repeated antigen encounters, which inevitably induces progressive T-cell differentiation and the loss of longevity. In this study, we identified PR domain zinc finger protein 1 (PRDM1) ie, Blimp-1, as a key epigenetic gene associated with terminal T-cell differentiation. The genetic knockout of PRDM1 by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) supported the maintenance of an early memory phenotype and polyfunctional cytokine secretion in repeatedly stimulated chimeric antigen receptor (CAR)-engineered T cells. PRDM1 disruption promoted the expansion of less differentiated memory CAR-T cells in vivo, which enhanced T-cell persistence and improved therapeutic efficacy in multiple tumor models. Mechanistically, PRDM1-ablated T cells displayed enhanced chromatin accessibility of the genes that regulate memory formation, thereby leading to the acquisition of gene expression profiles representative of early memory T cells. PRDM1 knockout also facilitated maintaining an early memory phenotype and cytokine polyfunctionality in T-cell receptor-engineered T cells as well as tumor-infiltrating lymphocytes. In other words, targeting PRDM1 enabled the generation of superior antitumor T cells, which is potentially applicable to a wide range of adoptive cancer immunotherapies.

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CAMK2G is identified as a novel therapeutic target for myelofibrosis

Miyauchi M., Sasaki K., Kagoya Y., Taoka K., Masamoto Y., Yamazaki S., Arai S., Mizuno H., Kurokawa M.

Blood Advances （Blood Advances）  6 （ 5 ） 1585 - 1597 2022年03月

査読有り,  ISSN  2473-9529

　概要を見る

Although JAK1/2 inhibition is effective in alleviating symptoms of myelofibrosis (MF), it does not result in the eradication of MF clones, which can lead to inhibitor-resistant clones emerging during the treatment. Here, we established induced pluripotent stem cells (iPSCs) derived from MF patient samples (MF-iPSCs) harboring JAK2 V617F, CALR type 1, or CALR type 2 mutations. We demonstrated that these cells faithfully recapitulate the drug sensitivity of the disease. These cells were used for chemical screening, and calcium/ calmodulin-dependent protein kinase 2 (CAMK2) was identified as a promising therapeutic target. MF model cells and mice induced by MPL W515L, another type of mutation recurrently detected in MF patients, were used to elucidate the therapeutic potential of CAMK2 inhibition. CAMK2 inhibition was effective against JAK2 inhibitor-sensitive and JAK2 inhibitor-resistant cells. Further research revealed CAMK2 g subtype was important in MF model cells induced by MPL W515L. We showed that CAMK2G hetero knockout in the primary bone marrow cells expressing MPL W515L decreased colony-forming capacity. CAMK2G inhibition with berbamine, a CAMK2G inhibitor, significantly prolonged survival and reduced disease phenotypes, such as splenomegaly and leukocytosis in a MF mouse model induced by MPL W515L. We investigated the molecular mechanisms underlying the therapeutic effect of CAMK2G inhibition and found that CAMK2G is activated by MPL signaling in MF model cells and is an effector in the MPL-JAK2 signaling pathway in these cells. These results indicate CAMK2G plays an important role in MF, and CAMK2G inhibition may be a novel therapeutic strategy that overcomes resistance to JAK1/2 inhibition.

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次世代CAR-T細胞療法の開発動向

籠谷 勇紀

臨床血液 63 （ 9 ） 1290 - 1297 2022年

筆頭著者, 最終著者, 責任著者, 査読有り

Universal CAR-T cellの開発動向について

籠谷 勇紀, 平野 直人

臨床血液 63 （ 7 ） 782 - 789 2022年

筆頭著者, 最終著者, 責任著者, 査読有り

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CD62L expression level determines the cell fate of myeloid progenitors

Ito Y., Nakahara F., Kagoya Y., Kurokawa M.

Stem Cell Reports （Stem Cell Reports）  16 （ 12 ） 2871 - 2886 2021年12月

査読有り,  ISSN  2213-6711

　概要を見る

Hematopoietic cells differentiate through several progenitors in a hierarchical manner, and recent single-cell analyses have revealed substantial heterogeneity within each progenitor. Although common myeloid progenitors (CMPs) are defined as a multipotent cell population that can differentiate into granulocyte-monocyte progenitors (GMPs) and megakaryocyte-erythrocyte progenitors (MEPs), and GMPs generate neutrophils and monocytes, these myeloid progenitors must contain some lineage-committed progenitors. Through gene expression analysis at single-cell levels, we identified CD62L as a marker to reveal the heterogeneity. We confirmed that CD62L-negative CMPs represent “bona fide” CMPs, whereas CD62L-high CMPs are mostly restricted to GMP potentials both in mice and humans. In addition, we identified CD62L-negative GMPs as the most immature subsets in GMPs and Ly6C+CD62L-intermediate and Ly6C+CD62L-high GMPs are skewed to neutrophil and monocyte differentiation in mice, respectively. Our findings contribute to more profound understanding about the mechanism of myeloid differentiation.

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Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation

Mizuno H., Koya J., Masamoto Y., Kagoya Y., Kurokawa M.

Cancer Science （Cancer Science）  112 （ 10 ） 4112 - 4126 2021年10月

査読有り,  ISSN  1347-9032

　概要を見る

Evi1 is a transcription factor essential for the development as well as progression of acute myeloid leukemia (AML) and high Evi1 AML is associated with extremely poor clinical outcome. Since targeting metabolic vulnerability is the emerging therapeutic strategy of cancer, we herein investigated a novel therapeutic target of Evi1 by analyzing transcriptomic, epigenetic, and metabolomic profiling of mouse high Evi1 leukemia cells. We revealed that Evi1 overexpression and Evi1-driven leukemic transformation upregulate transcription of gluconeogenesis enzyme Fbp1 and other pentose phosphate enzymes with interaction between Evi1 and the enhancer region of these genes. Metabolome analysis using Evi1-overexpressing leukemia cells uncovered pentose phosphate pathway upregulation by Evi1 overexpression. Suppression of Fbp1 as well as pentose phosphate pathway enzymes by shRNA-mediated knockdown selectively decreased Evi1-driven leukemogenesis in vitro. Moreover, pharmacological or shRNA-mediated Fbp1 inhibition in secondarily transplanted Evi1-overexpressing leukemia mouse significantly decreased leukemia cell burden. Collectively, targeting FBP1 is a promising therapeutic strategy of high Evi1 AML.

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