Publications by authors named "Yoshikane Kikushige"

53 Publications

A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.

Blood Adv 2021 Oct 12. Epub 2021 Oct 12.

Kyushu University Hospital, Japan.

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, 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 here 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004618DOI Listing
October 2021

Granulocyte collection by polymorphonuclear cell-targeting apheresis with medium-molecular-weight hydroxyethyl starch.

Int J Hematol 2021 Aug 28. Epub 2021 Aug 28.

Center for Cellular and Molecular Medicine, Kyushu University Hospital, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Granulocyte transfusion (GTX) is a therapeutic option for patients with prolonged neutropenia suffering from severe infections. Efficient granulocyte collection by apheresis from donors requires clear separation of granulocytes from red blood cells (RBCs), and infusion of high-molecular-weight (MW) hydroxyethyl starch (HES) facilitates RBC sedimentation. Recent research has shown that apheresis with medium-MW HES may prevent adverse effects of high-MW HES on donors, but the rationale for collection with medium-MW HES has yet to be evaluated. To validate the use of medium-MW HES, we first performed experiments with whole blood samples to determine how efficiently high-, medium- and low-MW HES separated granulocytes from RBCs, and found that medium-MW HES was just as efficient as high-MW HES. We also reviewed clinical data of granulocyte apheresis at our institution to evaluate granulocyte yields. Retrospective analysis of granulocyte collection revealed that apheresis with medium-MW HES yielded sufficient granulocytes for GTX and that donor anemia reduced collection efficiency. These results collectively may help us to establish a safer method for apheresis targeting polymorphonuclear granulocytes as an alternative to high-MW HES.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-021-03207-6DOI Listing
August 2021

TIM-3 in normal and malignant hematopoiesis: Structure, function, and signaling pathways.

Cancer Sci 2021 Sep 14;112(9):3419-3426. Epub 2021 Jul 14.

Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.

Acute myeloid leukemia (AML) is hierarchically organized by self-renewing leukemic stem cells (LSCs). LSCs originate from hematopoietic stem cells (HSCs) by acquiring multistep leukemogenic events. To specifically eradicate LSCs, while keeping normal HSCs intact, the discrimination of LSCs from HSCs is important. We have identified T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) as an LSC-specific surface molecule in human myeloid malignancies and demonstrated its essential function in maintaining the self-renewal ability of LSCs. TIM-3 has been intensively investigated as a "coinhibitory" or "immune checkpoint" molecule of T cells. However, little is known about its distinct function in T cells and myeloid malignancies. In this review, we discuss the structure of TIM-3 and its function in normal blood cells and LSCs, emphasizing the specific signaling pathways involved, as well as the therapeutic applications of TIM-3 molecules in human myeloid malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.15042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409405PMC
September 2021

[Cytotoxic chemotherapy for AML in adults].

Rinsho Ketsueki 2020 ;61(9):1138-1149

Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences.

Genomics and novel molecularly targeted drugs for treating acute myelogenous leukemia (AML) are developing rapidly. To optimize the allocation of patients to the best possible treatment, we have to expedite test results of cytogenetic and molecular analyses for target mutations such as CBF and FLT3, since gene mutations are specifically associated with patient prognosis and therefore inform medical decision making. However, novel agents cannot completely eradicate AML because of the emergence of resistance to these agents; therefore, at the moment it is still necessary to combine cytotoxic treatment with novel agents. Hence, it becomes vital to understand how to stratify AML patients and subsequently treat the right patients with the right combination of cytotoxic treatments and novel agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.61.1138DOI Listing
January 2021

Pathogenesis of chronic lymphocytic leukemia and the development of novel therapeutic strategies.

J Clin Exp Hematop 2020 Dec 4;60(4):146-158. Epub 2020 Nov 4.

Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is characterized by the clonal expansion of mature CD5 B cells. There have been substantial advances in the field of CLL research in the last decade, including the identification of recurrent mutations, and clarification of clonal architectures, signaling molecules, and the multistep leukemogenic process, providing a comprehensive understanding of CLL pathogenesis. Furthermore, the development of therapeutic approaches, especially that of molecular target therapies against CLL, has markedly improved the standard of care for CLL. This review focuses on the recent insights made in CLL leukemogenesis and the development of novel therapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3960/jslrt.20036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810248PMC
December 2020

Correction to: Measurable residual disease after the first consolidation predicts the outcomes of patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy.

Int J Hematol 2020 Sep;112(3):431-432

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

In the original publication of the article, the "CNS involvement" in the last row under the column "Total N=50" has been published incorrectly. The correct Table 1 is given in this correction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-02932-8DOI Listing
September 2020

Measurable residual disease after the first consolidation predicts the outcomes of patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy.

Int J Hematol 2020 Sep 10;112(3):349-360. Epub 2020 Jun 10.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

We stratified patients with newly diagnosed acute promyelocytic leukemia (APL) according to a white blood cell (WBC) count of ≥ 3 × 10/L (high risk) or < 3 × 10/L (low risk) before administering risk-adapted chemotherapy in combination with all-trans retinoic acid (ATRA). In total, 27 low-risk and 23 high-risk patients were assigned to receive induction and three courses of consolidation with ATRA and anthracycline, followed by 2-year maintenance regimen. High-risk group additionally received cytarabine during 1st consolidation and another one-shot idarubicin treatment during 3rd consolidation. We prospectively monitored measurable residual disease (MRD) after induction and each consolidation. In the low-risk and high-risk groups, 5-year disease-free survival (DFS) rates were 86.5% and 81.2% (p = 0.862), and 5-year overall survival rates were 100% and 84.8% (p = 0.062), respectively. In the MRD-negative and MRD-positive groups, 5-year DFS rates were 91.7% and 78.4% (p = 0.402) and 84.7% and 60.0% (p = 0.102) after induction and 1st consolidation, respectively. Relapse rates were 8.3% and 13.3% (p = 0.570) and 9.0% and 40.0% (p = 0.076) after induction and 1st consolidation, respectively. Achieving MRD-negativity after 1st consolidation, rather than after induction, was a potential predictor of relapse and DFS in patients with APL treated with ATRA + chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-02911-zDOI Listing
September 2020

Tyrosine kinase inhibitors induce alternative spliced BCR-ABL variant via inhibition of RNA polymerase II on genomic BCR-ABL.

Cancer Sci 2020 Jul 14;111(7):2361-2373. Epub 2020 Jun 14.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.

To elucidate dynamic changes in native BCR-ABL and alternatively spliced tyrosine kinase inhibitor (TKI)-resistant but function-dead BCR-ABL variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such BCR-ABL variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing BCR-ABL , accounting for 0.8% of the total IS BCR-ABL, corresponding to actual BCR-ABL value of 1.1539% IS. TKI rapidly decreased native BCR-ABL but not BCR-ABL , leading to the initial increase in the proportion of BCR-ABL . Thereafter, both native BCR-ABL and BCR-ABL gradually decreased in the course of TKI treatment, whereas small populations positive for TKI-resistant BCR-ABL continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native BCR-ABL clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function-dead BCR-ABL , suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis-splicing BCR-ABL , occurring at the particular pseudo-splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional BCR-ABL extracting BCR-ABL would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385367PMC
July 2020

Aromatase is a novel neosubstrate of cereblon responsible for immunomodulatory drug-induced thrombocytopenia.

Blood 2020 06;135(24):2146-2158

Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.

Immunomodulatory drugs (IMiDs) are key agents for the treatment of multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the recruitment of neosubstrates to cereblon, a substrate receptor of the E3 ubiquitin ligase complex; therefore, identification of cell-specific neosubstrates is important to understand the effects of IMiDs. In clinical practice, IMiDs induce thrombocytopenia, which frequently results in the discontinuation of IMiD treatment. In the current study, we sought to identify the molecular mechanism underlying thrombocytopenia induced by IMiD treatment. We found that IMiDs strongly impaired proplatelet formation, a critical step in functional platelet production, through the inhibition of autocrine estradiol signaling in human megakaryocytes. Furthermore, we identified aromatase, an indispensable enzyme for estradiol biosynthesis, as a novel neosubstrate of cereblon. IMiDs promoted the recruitment of aromatase to cereblon, resulting in the degradation of aromatase in a proteasome-dependent manner. Finally, aromatase was significantly degraded in the bone marrow of patients with multiple myeloma who developed thrombocytopenia with IMiD treatment. These data suggest that aromatase is a neosubstrate of cereblon that is responsible for IMiD-induced thrombocytopenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019003749DOI Listing
June 2020

A human SIRPA knock-in xenograft mouse model to study human hematopoietic and cancer stem cells.

Blood 2020 05;135(19):1661-1672

Hematology, Clinical Immunology, and Infectious Diseases, Ehime University Graduate School of Medicine, Ehime, Japan.

In human-to-mouse xenogeneic transplantation, polymorphisms of signal-regulatory protein α (SIRPA) that decide their binding affinity for human CD47 are critical for engraftment efficiency of human cells. In this study, we generated a new C57BL/6.Rag2nullIl2rgnull (BRG) mouse line with Sirpahuman/human (BRGShuman) mice, in which mouse Sirpa was replaced by human SIRPA encompassing all 8 exons. Macrophages from C57BL/6 mice harboring Sirpahuman/human had a significantly stronger affinity for human CD47 than those harboring SirpaNOD/NOD and did not show detectable phagocytosis against human hematopoietic stem cells. In turn, Sirpahuman/human macrophages had a moderate affinity for mouse CD47, and BRGShuman mice did not exhibit the blood cytopenia that was seen in Sirpa-/- mice. In human to mouse xenograft experiments, BRGShuman mice showed significantly greater engraftment and maintenance of human hematopoiesis with a high level of myeloid reconstitution, as well as improved reconstitution in peripheral tissues, compared with BRG mice harboring SirpaNOD/NOD (BRGSNOD). BRGShuman mice also showed significantly enhanced engraftment and growth of acute myeloid leukemia and subcutaneously transplanted human colon cancer cells compared with BRGSNOD mice. BRGShuman mice should be a useful basic line for establishing a more authentic xenotransplantation model to study normal and malignant human stem cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019002194DOI Listing
May 2020

Pathophysiology of chronic lymphocytic leukemia and human B1 cell development.

Int J Hematol 2020 May 3;111(5):634-641. Epub 2019 Dec 3.

Department of Medicine and Biosystemic Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.

Chronic lymphocytic leukemia (CLL), the most frequent type of leukemia in adults, is a lymphoproliferative disease characterized by the clonal expansion of mature CD5 B cells in peripheral blood, bone marrow, and secondary lymphoid tissues. Over the past decade, substantial advances have been made in understanding the pathogenesis of CLL, including the identification of recurrent mutations, and clarification of clonal architectures, transcriptome analyses, and the multistep leukemogenic process. The biology of CLL is now better understood. The present review focuses on recent insights into CLL leukemogenesis, emphasizing the role of genetic lesions, and the multistep process initiating from very immature hematopoietic stem cells. Finally, we also review progress in the study of human B1 B cells, the putative normal counterparts of CLL cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-019-02788-7DOI Listing
May 2020

Anti-GPRC5D/CD3 Bispecific T-Cell-Redirecting Antibody for the Treatment of Multiple Myeloma.

Mol Cancer Ther 2019 09 3;18(9):1555-1564. Epub 2019 Jul 3.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Although treatment advances over recent decades have significantly improved survival of patients with multiple myeloma, there is still an unmet medical need for more effective treatments. In this study, we identified G-protein-coupled receptor family C group 5 member D (GPRC5D) expression on the surface of malignant cells involved in multiple myeloma, but except for plasma cells and B cells, not at appreciable levels on normal hematopoietic cells and bone marrow progenitors, including hematopoietic stem cells. In addition, we constructed IgG-based anti-GPRC5D/CD3 bispecific T-cell-redirecting antibodies (GPRC5D TRAB), which suppressed the tumor growth of GPRC5D-positive myeloma cells through the activation of T cells and in xenograft models. Collectively, these findings suggest that GPRC5D is an antigen specific to multiple myeloma and a potential target of TRAB therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-1216DOI Listing
September 2019

Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer.

Oncogene 2019 02 4;38(6):780-793. Epub 2018 Sep 4.

Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Cancer stem cells (CSCs) possess the capacity for self-renewal and the potential to differentiate into non-CSCs. The recent discoveries of dynamic equilibrium between CSCs and non-CSCs revealed the significance of acquiring CSC-like properties in non-CSCs as an important process in progression of cancer. The mechanism underlying acquisition of CSC-like properties has mainly been investigated in the context of epithelial-mesenchymal transition. Here, we demonstrate the dedifferentiation process may be an alternative mechanism in acquisition of CSC-like properties in human colorectal cancer cells. By exploring the single-cell gene expression analysis of organoids developed from CD44 CSCs, we identified TWIST1 as a key molecule for maintaining the undifferentiated state of cancer cells. Consistent with the finding, we found that TGF-beta signaling pathway, a regulator of TWIST1, was specifically activated in the undifferentiated CD44 CSCs in human colorectal cancer using microarray-based gene expression analysis and quantitative pathology imaging system. Furthermore, we showed that external stimulation with TGF-beta and the induction of TWIST1 converted CD44 non-CSCs into the undifferentiated CD44 CSCs, leading to the significant increment of CSCs in xenograft models. This study strongly suggests dedifferentiation driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-018-0480-0DOI Listing
February 2019

Human Herpes Virus-6-Associated Encephalitis/Myelitis Mimicking Calcineurin Inhibitor-Induced Pain Syndrome in Allogeneic Stem Cell Transplantation Recipients.

Biol Blood Marrow Transplant 2018 12 17;24(12):2540-2548. Epub 2018 Jul 17.

Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.. Electronic address:

Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor-induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve-related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve-related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; P = .049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; P = .036), whereas there was no significant difference among the latter 2 groups (P = .889). The development of HHV6-associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve-related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2018.07.017DOI Listing
December 2018

E‑cadherin regulates proliferation of colorectal cancer stem cells through NANOG.

Oncol Rep 2018 Aug 24;40(2):693-703. Epub 2018 May 24.

Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan.

Cancer stem cells (CSCs) possess a self‑renewal ability and display tumorigenic potential in immunodeficient mice. Colorectal CSCs are thought to be a uniform population and no functionally distinct subpopulations have been identified. Because E‑cadherin is an essential molecule for self‑renewal of embryonic stem cells, we examined E‑cadherin expression, which may play a role in maintaining the properties of CSCs, in EpCAMhigh/CD44+ colorectal CSCs from human primary colorectal cancers. We obtained 18 surgical specimens of human primary colorectal cancer. CD44, EpCAM, and E‑cadherin expression were analyzed by fluorescence‑activated cell sorting. Sorted EpCAMhigh/CD44+ colorectal CSCs were injected into immunodeficient mice to estimate the tumorigenic potential. Genetic profiles were analyzed by cDNA microarray. Notably, colorectal CSCs could be divided into two populations based on the E‑cadherin expression status, and they exhibited different pathological characteristics. Compared to E‑cadherin‑negative colorectal CSCs, E‑cadherin‑positive (EC+) colorectal CSCs demonstrated higher tumor growth potential in vivo. EC+ colorectal CSCs revealed a higher expression of the pluripotency factor NANOG, which contributed to the higher tumor growth potential of EC+ colorectal CSCs through control of cyclin D1 expression. These findings are the first demonstration of functionally distinct subpopulations of colorectal CSCs in human clinical samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/or.2018.6464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072297PMC
August 2018

Frontline treatment of AML in adults.

Rinsho Ketsueki 2017 ;58(10):1884-1894

Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science.

Despite recent progress in diagnosis and leukemogenesis based on genomic landscapes in acute myelogenous leukemia (AML), advances in AML treatment lag behind. Over the past four decades, combination chemotherapy with anthracycline and cytarabine remains the standard induction therapy. Subsequent post-remission consolidation therapy stratifies patients into favorable-risk, intermediate-risk, and unfavorable-risk groups to assign post-remission therapies based on cytogenetic abnormalities and molecular mutations. Allogeneic stem-cell transplant decreases the risk of AML recurrence compared to standard chemotherapy, but it also raises the risk of serious complications. Recent large collections of matched genomic and clinical data may assist in selecting the best individualized therapy for each AML patient. Emerging evidence indicates that molecularly targeted therapies such as FLT3 and IDH inhibitors may be effective in distinct AML subtypes, providing further rationale for a personalized medicine approach. An umbrella trial, such as "BEAT AML Master Trial," designed to offer novel targeted therapy to AML patients based on their genetic characteristics, will be launching worldwide in the near future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.58.1884DOI Listing
December 2017

Progress in the leukemic stem cell study and a novel therapeutic approach targeting leukemic stem cells.

Rinsho Ketsueki 2017 ;58(10):1838-1843

Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science.

Hematopoietic stem cells (HSCs) have the potential to self-renew and differentiate into multi-lineage mature hematopoietic cells; thus, these cells can maintain hematopoiesis. Human HSCs reside within the CD34CD38 cell fractions. Similarly, in acute myelogenous leukemia (AML), a small number of leukemic cells, called leukemic stem cells (LSCs), can be enriched within the identical CD34CD38 cell fractions. LSCs can self-renew and produce clonogenic leukemic cells, whereas non-LSCs lack the potential to self-renew or maintain leukemia; thus, AML is organized as a hierarchy that originated from LSCs. LSCs play a central role in the maintenance and progression of leukemia; therefore, these cells should be an ultimate target for the eradication of human AML. Previous studies have revealed specific molecular machineries essential for LSCs. Targeting LSC-specific molecules should be a good therapeutic approach to kill LSCs without affecting normal cells. In this review, we would like to introduce the recent progress in the LSC study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.58.1838DOI Listing
December 2017

Identification of unipotent megakaryocyte progenitors in human hematopoiesis.

Blood 2017 06 23;129(25):3332-3343. Epub 2017 Mar 23.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; and.

The developmental pathway for human megakaryocytes remains unclear, and the definition of pure unipotent megakaryocyte progenitor is still controversial. Using single-cell transcriptome analysis, we have identified a cluster of cells within immature hematopoietic stem- and progenitor-cell populations that specifically expresses genes related to the megakaryocyte lineage. We used CD41 as a positive marker to identify these cells within the CD34CD38IL-3RαCD45RA common myeloid progenitor (CMP) population. These cells lacked erythroid and granulocyte-macrophage potential but exhibited robust differentiation into the megakaryocyte lineage at a high frequency, both in vivo and in vitro. The efficiency and expansion potential of these cells exceeded those of conventional bipotent megakaryocyte/erythrocyte progenitors. Accordingly, the CD41 CMP was defined as a unipotent megakaryocyte progenitor (MegP) that is likely to represent the major pathway for human megakaryopoiesis, independent of canonical megakaryocyte-erythroid lineage bifurcation. In the bone marrow of patients with essential thrombocythemia, the MegP population was significantly expanded in the context of a high burden of Janus kinase 2 mutations. Thus, the prospectively isolatable and functionally homogeneous human MegP will be useful for the elucidation of the mechanisms underlying normal and malignant human hematopoiesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2016-09-741611DOI Listing
June 2017

Mobilization of human immature hematopoietic progenitors through combinatory use of bortezomib and immunomodulatory drugs.

Int J Hematol 2017 Apr 21;105(4):423-432. Epub 2016 Nov 21.

Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.

Combination use of the proteasome inhibitor bortezomib and the immunomodulatory drugs lenalidomide or thalidomide has provided superior outcomes in multiple myeloma over their single use; however, these combinations can produce significant toxicities. Unexpectedly, we found a small but significant increase in the population of immature granulocytes and erythrocytes/megakaryocytes in peripheral blood in 16 of 22 patients (73%) treated with dexamethasone in combination with bortezomib and immunomodulatory drugs (triplet), but not in any of 25 patients treated with either bortezomib or immunomodulatory drugs with dexamethasone (doublet). These immature cells gradually increased to a peak level (mean 2.6% per white blood cells) with triplet therapy, and disappeared immediately after therapy cessation. The numbers of circulating CD34 cells and colony-forming cells derived from peripheral blood mononuclear cells increased after triplet therapy compared with those in patients treated by either bortezomib or immunomodulatory drugs plus dexamethasone. Furthermore, triplet regimen downregulated the expression of CXCR4, a chemokine receptor essential for bone marrow retention, on CD34 cells, suggesting an unexpected effect on normal hematopoietic stem/progenitor cells through the reduced interaction with the bone marrow microenvironment. Our observations suggest that combination use should be carefully evaluated to exert synergistic anti-myeloma effects while avoiding unexpected adverse events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-016-2148-2DOI Listing
April 2017

Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with Kit(Wv) Mutations.

Stem Cell Reports 2016 09 4;7(3):425-438. Epub 2016 Aug 4.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan. Electronic address:

In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous Kit(Wv) mutations into C57BL/6.Rag2(null)Il2rg(null) mice with NOD-Sirpa (BRGS) strongly promoted human multi-lineage reconstitution. After xenotransplantation of human CD34(+)CD38(-) cord blood cells, these newly generated C57BL/6.Rag2(null)Il2rg(null)NOD-Sirpa Kit(Wv/Wv) (BRGSK(Wv/Wv)) mice showed significantly higher levels of human cell chimerism and long-term multi-lineage reconstitution compared with BRGS mice. Strikingly, this mouse displayed a robust reconstitution of human erythropoiesis and thrombopoiesis with terminal maturation in the bone marrow. Furthermore, depletion of host macrophages by clodronate administration resulted in the presence of human erythrocytes and platelets in the circulation. Thus, attenuation of mouse KIT signaling greatly enhances the multi-lineage differentiation of human hematopoietic stem and progenitor cells (HSPCs) in mouse bone marrow, presumably by outcompeting mouse HSPCs to occupy suitable microenvironments. The BRGSK(Wv/Wv) mouse model is a useful tool to study human multi-lineage hematopoiesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stemcr.2016.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031955PMC
September 2016

[A TIM-3/galectin-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemia progression].

Rinsho Ketsueki 2016 Apr;57(4):412-6

Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science.

Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. We previously reported that the T-cell immunoglobulin mucin-3 (TIM-3) is expressed on the LCS surface in most types of AML. Since only the TIM-3(+), i.e. not the TIM-3(-), fraction of human AML cells can reconstitute human AML in immunodeficient mice, we hypothesized that the TIM-3 has an essential function in maintaining AML LSCs. Herein, we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for human AML LSC development. Serum Gal-9 was significantly elevated in primary AML patients and in mice xenografted with human AML. Neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML, as well as Gal-9 ligation of TIM-3 co-activated NF-κB and β-catenin signaling, suggesting that TIM-3 signaling is necessary for LSC self-renewal. Interestingly, identical changes were found to be involved in the progressive transformation of a variety of pre-leukemic disorders into myeloid leukemia. Thus, molecules constituting the TIM-3/Gal-9 autocrine loop are potential therapeutic targets applicable to most types of myeloid leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.57.412DOI Listing
April 2016

Identification of TIM-3 as a Leukemic Stem Cell Surface Molecule in Primary Acute Myeloid Leukemia.

Oncology 2015 10;89 Suppl 1:28-32. Epub 2015 Nov 10.

Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.

Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target in AML. Eradication of LSCs should be a critical and efficient therapeutic approach for the cure of AML. T-cell immunoglobulin mucin-3 (TIM-3) is expressed in most types of AML LSCs, but not in normal hematopoietic stem cells (HSCs); therefore, TIM-3 would be one of the promising therapeutic targets to specifically kill AML LSCs, sparing normal HSCs. In xenograft models reconstituted with human AML LSCs or human normal HSCs, an anti-human TIM-3 mouse antibody with cytotoxic activities exerts a potent anti-leukemic effect by targeting AML LSCs but does not affect normal human hematopoiesis in vivo. Here, we would like to introduce the recent studies on TIM-3 in normal and malignant hematopoiesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000431062DOI Listing
February 2016

A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression.

Cell Stem Cell 2015 Sep 13;17(3):341-52. Epub 2015 Aug 13.

Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan. Electronic address:

Signaling mechanisms underlying self-renewal of leukemic stem cells (LSCs) are poorly understood, and identifying pathways specifically active in LSCs could provide opportunities for therapeutic intervention. T-cell immunoglobin mucin-3 (TIM-3) is expressed on the surface of LSCs in many types of human acute myeloid leukemia (AML), but not on hematopoietic stem cells (HSCs). Here, we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for LSC self-renewal and development of human AML. Serum Gal-9 levels were significantly elevated in AML patients and in mice xenografted with primary human AML samples, and neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML. Gal-9-mediated stimulation of TIM-3 co-activated NF-κB and β-catenin signaling, pathways known to promote LSC self-renewal. These changes were further associated with leukemic transformation of a variety of pre-leukemic disorders and together highlight that targeting the TIM-3/Gal-9 autocrine loop could be a useful strategy for treating myeloid leukemias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stem.2015.07.011DOI Listing
September 2015

[Molecular targeted therapy for leukemic stem cells].

Nihon Rinsho 2015 May;73(5):811-5

Acute myelogenous leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. LSCs play a central role in the propagation of leukemia through their unique stem cell like properties, and LSCs share the many functional molecules with their normal counterpart hematopoietic stem cells (HSCs). For the establishment of LSCs-specific therapeutic approaches, it is quite important to understand the biological differences between LSCs and HSCs. Recent, studies have succeeded in clarifying these biological differences. In this review, I would like to introduce the biological significance of LSCs and discuss the molecular targeted therapy against LSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
May 2015

Pre-malignant lymphoid cells arise from hematopoietic stem/progenitor cells in chronic lymphocytic leukemia.

Int J Hematol 2015 Nov 3;102(5):528-35. Epub 2015 Feb 3.

Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.

Human malignancies progress through a multistep process that includes the development of critical somatic mutations over the clinical course. Recent novel findings have indicated that hematopoietic stem cells (HSCs), which have the potential to self-renew and differentiate into multilineage hematopoietic cells, are an important cellular target for the accumulation of critical somatic mutations in hematological malignancies and play a central role in myeloid malignancy development. In contrast to myeloid malignancies, mature lymphoid malignancies, such as chronic lymphocytic leukemia (CLL), are thought to originate directly from differentiated mature lymphocytes; however, recent compelling data have shown that primitive HSCs and hematopoietic progenitor cells contribute to the pathogenesis of mature lymphoid malignancies. Several representative mutations of hematological malignancies have been identified within the HSCs of CLL and lymphoma patients, indicating that the self-renewing long-lived fraction of HSCs can serve as a reservoir for the development of oncogenic events. Novel mice models have been established as human mature lymphoma models, in which specific oncogenic events target the HSCs and immature progenitor cells. These data collectively suggest that HSCs can be the cellular target involved in the accumulation of oncogenic events in the pathogenesis of mature lymphoid and myeloid malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-015-1740-1DOI Listing
November 2015

CD41 marks the initial myelo-erythroid lineage specification in adult mouse hematopoiesis: redefinition of murine common myeloid progenitor.

Stem Cells 2015 Mar;33(3):976-87

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Previous studies have predicted that reciprocal activation of GATA-1 and PU.1 regulates myelo-erythroid versus myelo-lymphoid lineage commitment in early hematopoiesis. Such PU.1-activating myelo-lymphoid progenitors exist within the lymphoid-primed multipotent progenitor (LMPP) population at the primitive Lineage(-) Sca-1(+) c-Kit(+) (LSK) stage. We here show that the counterpart of GATA-1-activating myelo-erythroid progenitor resides also at the LSK stage, expressing CD41 at a high level. Purified CD41(hi) LSK cells showed exceedingly strong and prolonged myelo-erythroid-restricted reconstitution, and primed myelo-erythroid gene expression with a more primitive molecular signature as compared to the original common myeloid progenitor (CMP). The CD41(hi) LSK cells more strongly contributed to emergent and malignant myelopoiesis than LMPPs, and produced the original CMP by downregulating Sca-1 and CD41, suggesting that they are the earliest CMPs. Thus, the hematopoietic developmental map should be revised by integrating the primary branchpoint comprised of the new, isolatable CD41(hi) CMP and the LMPP populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/stem.1906DOI Listing
March 2015

The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell.

Exp Hematol 2014 Nov 4;42(11):955-65.e1-5. Epub 2014 Aug 4.

Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan; Center for Cellular and Molecular Medicine, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan. Electronic address:

The cellular properties of leukemia stem cells (LSCs) are achieved at least through Class I and Class II mutations that generate signals for enhanced proliferation and impaired differentiation, respectively. Here we show that in t(8;21) acute myelogenous leukemia (AML), hematopoietic stem cells (HSCs) transform into LSCs via definitively-ordered acquisition of Class II (AML1/ETO) and then Class I (c-KIT mutant) abnormalities. Six t(8;21) AML patients with c-KIT mutants maintaining > 3 years of complete remission were analyzed. At diagnosis, all single LSCs had both AML1/ETO and c-KIT mutations. However, in remission, 16 out of 1,728 CD34(+)CD38(-) HSCs and 89 out of 7,187 single HSC-derived myeloerythroid colonies from these patients had AML1/ETO, whose breakpoints were identical to those found in LSCs. These cells had wild-type c-KIT, which expressed AML1/ETO at a low level, and could differentiate into mature blood cells, suggesting that they may be the persistent preleukemic stem cells. Microarray analysis suggested that mutated c-KIT signaling provides LSCs with enhanced survival and proliferation. Thus, in t(8;21) AML, the acquisition of AML1/ETO is not sufficient, and the subsequent upregulation of AML1/ETO and the additional c-KIT mutant signaling are critical steps for transformation into LSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exphem.2014.07.267DOI Listing
November 2014

Hematopoietic stem cell aging and chronic lymphocytic leukemia pathogenesis.

Int J Hematol 2014 Oct 7;100(4):335-40. Epub 2014 Aug 7.

Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.

Human malignancies develop through the multistep acquisition of critical somatic mutations during the clinical course. Regarding hematological malignancies, recent novel findings have indicated that hematopoietic stem cells (HSCs), which have the potential to self-renew and differentiate into multilineage hematopoietic cells, are an important cellular target for the accumulation of critical somatic mutations and play a central role in myeloid malignancy development. In contrast to myeloid malignancies, mature lymphoid malignancies, such as chronic lymphocytic leukemia (CLL), are considered to directly originate from differentiated mature lymphocytes; however, we previously reported that the propensity to generate clonal B cells had already been acquired at the HSC stage in CLL patients. Similarly, HSC involvement has been reported in the pathogenesis of mature T cell lymphomas. These studies indicate that, in mature lymphoid, if not all, malignancies, HSCs should be considered as the critical cellular target in the oncogenic process. The prevalence of these hematological malignancies dramatically increases with age, and the effect of aging HSCs should thus be taken into account when investigating the stepwise malignant transformation process of these age-associated malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-014-1651-6DOI Listing
October 2014

Acquired initiating mutations in early hematopoietic cells of CLL patients.

Cancer Discov 2014 Sep 11;4(9):1088-101. Epub 2014 Jun 11.

Institut National de la Santé et de la Recherche Medicale (INSERM) U985; Institut Gustave Roussy, Villejuif; Ligue Nationale Contre le Cancer, Equipe labellisée, Paris; Université Paris-Sud;

Unlabelled: Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase.

Significance: The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-14-0104DOI Listing
September 2014

Successful treatment of invasive zygomycosis based on a prompt diagnosis using molecular methods in a patient with acute myelogenous leukemia.

Intern Med 2014 ;53(10):1087-91

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Japan.

Zygomycosis is a lethal and invasive mold infection that is often associated with hematological malignancies. The keys for successful treatment include making a rapid diagnosis and appropriately administering antifungal agents. We herein report the early diagnosis of a case of zygomycosis in a patient with acute myeloid leukemia using a deoxyribonucleic acid sequence analysis. We successfully performed allogeneic hematopoietic stem cell transplantation with the use of high-dose liposomal amphotericin B and granulocyte transfusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.53.1366DOI Listing
April 2015
-->