Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Lung inflammatory injury and tissue repair (Jul 2023)
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact

Hematologies

  • 340 Articles
  • 4 Posts
  • ← Previous
  • 1
  • 2
  • 3
  • …
  • 33
  • 34
  • Next →
Gestational diabetes in mice induces hematopoietic memory that impacts the long-term health of the offspring
Vinothini Govindarajah, … , Mei Xin, Damien Reynaud
Vinothini Govindarajah, … , Mei Xin, Damien Reynaud
Published November 21, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI169730.
View: Text | PDF

Gestational diabetes in mice induces hematopoietic memory that impacts the long-term health of the offspring

  • Text
  • PDF
Abstract

Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can be in part linked to hematopoietic alterations. Although they do not show any gross metabolic disruptions, the adult offspring maintain hematopoietic features associated with diabetes, indicating the acquisition of a lasting diabetic hematopoietic memory. We show that the induction of this hematopoietic memory during gestation relies on the activity of the AGER pattern recognition receptor and the NLRP3 inflammasome, which leads to increased placental inflammation. In adult offspring, we find that this memory is associated with DNMT1 upregulation and epigenetic changes in hematopoietic progenitors. Altogether, our results demonstrate that the hematopoietic system can acquire a lasting memory of gestational diabetes, and that this memory constitutes a new pathway connecting gestational health to adult pathologies.

Authors

Vinothini Govindarajah, Masahide Sakabe, Samantha Good, Michael Solomon, Ashok Arasu, Nong Chen, Xuan Zhang, H. Leighton Grimes, Ady Kendler, Mei Xin, Damien Reynaud

×

Targeting lysine demethylase 6B ameliorates ASXL1 truncation-mediated myeloid malignancies in preclinical models
Guo Ge, … , Mingjiang Xu, Feng-Chun Yang
Guo Ge, … , Mingjiang Xu, Feng-Chun Yang
Published November 2, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI163964.
View: Text | PDF

Targeting lysine demethylase 6B ameliorates ASXL1 truncation-mediated myeloid malignancies in preclinical models

  • Text
  • PDF
Abstract

ASXL1 mutation frequently occurs in all forms of myeloid malignancies and is associated with aggressive disease and poor prognosis. ASXL1 recruits Polycomb Repressive Complex 2 (PRC2) to specific gene loci to repress transcription through tri-methylation of histone H3 on lysine 27 (H3K27me3). ASXL1 alterations reduce H3K27me3 levels, which results in leukemogenic gene expression and the development of myeloid malignancies. Standard therapies for myeloid malignancies have limited efficacy when mutated ASXL1 is present. We discovered up-regulation of lysine demethylase 6B (KDM6B), a demethylase for H3K27me3, in ASXL1-mutant leukemic cells, which further reduces H3K27me3 levels and facilitates myeloid transformation. Here, we demonstrated that heterozygous deletion of Kdm6b restored H3K27me3 levels and normalized dysregulated gene expression in Asxl1Y588XTg hematopoietic stem/progenitor cells (HSPCs). Furthermore, heterozygous deletion of Kdm6b decreased the HSPC pool, restored their self-renewal capacity, prevented biased myeloid differentiation, and abrogated progression to myeloid malignancies in Asxl1Y588XTg mice. Importantly, administration of GSK-J4, a KDM6B inhibitor, not only restored H3K27me3 levels but also reduced the disease burden in NSG mice xenografted with human ASXL1 mutant leukemic cells in vivo. This preclinical finding provides compelling evidence that targeting KDM6B may be a therapeutic strategy for myeloid malignancies with ASXL1 mutations.

Authors

Guo Ge, Peng Zhang, Pinpin Sui, Shi Chen, Hui Yang, Ying Guo, Ivan P. Rubalcava, Asra Noor, Caroline R. Delma, Joel Agosto-Peña, Hui Geng, Edward A. Medina, Ying Liang, Stephen D. Nimer, Ruben Mesa, Omar Abdel-Wahab, Mingjiang Xu, Feng-Chun Yang

×

Genome editing-induced t(4;11) chromosomal translocations model B cell precursor acute lymphoblastic leukemias with KMT2A-AFF1 fusion
Feng Pan, … , Kara L. Davis, Michael L. Cleary
Feng Pan, … , Kara L. Davis, Michael L. Cleary
Published November 2, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI171030.
View: Text | PDF

Genome editing-induced t(4;11) chromosomal translocations model B cell precursor acute lymphoblastic leukemias with KMT2A-AFF1 fusion

  • Text
  • PDF
Abstract

Authors

Feng Pan, Jolanda Sarno, Johan Jeong, Xin Yang, Astraea Jager, Tanja A. Gruber, Kara L. Davis, Michael L. Cleary

×

BCMA- and CST6-specific CAR T cells lyse multiple myeloma cells and suppress murine osteolytic lesions
Fumou Sun, … , John D. Shaughnessy Jr., Fenghuang Zhan
Fumou Sun, … , John D. Shaughnessy Jr., Fenghuang Zhan
Published October 26, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI171396.
View: Text | PDF

BCMA- and CST6-specific CAR T cells lyse multiple myeloma cells and suppress murine osteolytic lesions

  • Text
  • PDF
Abstract

We have previously demonstrated that cystatin E/M (CST6), elevated in a subset of multiple myeloma (MM) patients lacking osteolytic lesions (OL), suppresses MM bone disease by blocking osteoclast differentiation and function. CST6 is a secreted type 2 cystatin, a cysteine protease inhibitor that regulates lysosomal cysteine proteases and the asparaginyl endopeptidase legumain. We have developed B cell maturation antigen (BCMA)-CST6-chimeric antigen receptor (CAR) T cells, which lyse MM cells and release CST6 proteins. Our in vitro studies show that these CAR-T cells suppress differentiation and formation of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts. Using xenografted MM mice, bioluminescence images show that both BCMA-CAR-T and BCMA-CST6-CAR-T cells inhibit MM growth to a similar extent. Reconstructed micro-computed tomography (µCT) images reveal that BCMA-CST6-CAR-T cells, but not BCMA-CAR-T cells, prevent MM-induced bone damage and decrease osteoclast numbers. Our results provide a CAR-T strategy that targets tumor cells directly and delivers an inhibitor of bone resorption.

Authors

Fumou Sun, Yan Cheng, Jin-Ran Chen, Visanu Wanchai, David E. Mery, Hongwei Xu, Dongzheng Gai, Samer Al Hadidi, Carolina Schinke, Sharmilan Thanendrarajan, Maurizio Zangari, Frits van Rhee, Guido Tricot, John D. Shaughnessy Jr., Fenghuang Zhan

×

A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice
Adhithi Rajagopalan, … , Emery H. Bresnick, Jing Zhang
Adhithi Rajagopalan, … , Emery H. Bresnick, Jing Zhang
Published October 17, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI173116.
View: Text | PDF

A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice

  • Text
  • PDF
Abstract

We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have extremely poor prognosis, and most of these TP53 mutations are missense mutations. Here, we report that in contrast to mixed AML and T-cell malignancy developed in NrasG12D/+; p53-/- (NP-/-) mice, NrasG12D/+; p53R172H/+ (NPmut) mice rapidly developed an inflammation-associated AML. Under the inflammatory conditions, NPmut hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and largely normal cell proliferation despite MEK/ERK hyperactivation. RNA-Seq analysis revealed that oncogenic NRAS signaling and mutant p53 synergize to establish an NPmut-AML transcriptome distinct from that of NP-/- cells. The NPmut-AML transcriptome showed GATA2 downregulation and elevated expression of inflammatory genes, including those linked to NFκB signaling. NFκB was also upregulated in human NRAS;TP53 AML. Exogenous expression of GATA2 in human NPmut KY821 AML cells downregulated inflammatory gene expression. Mouse and human NPmut AML cells were sensitive to MEK and NFκB inhibition in vitro. The proteasome inhibitor bortezomib stabilized NFκB inhibitory protein IκBα reduced inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NPmut mice. Our study demonstrates that a p53 structural mutant synergizes with oncogenic NRAS to promote AML through mechanisms distinct from p53 loss.

Authors

Adhithi Rajagopalan, Yubin Feng, Meher B. Gayatri, Erik A. Ranheim, Taylor Klungness, Daniel R. Matson, Moon Hee Lee, Mabel Minji Jung, Yun Zhou, Xin Gao, Kalyan V.G. Nadiminti, David T. Yang, Vu L. Tran, Eric Padron, Shigeki Miyamoto, Emery H. Bresnick, Jing Zhang

×

Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies
Stephen Jun Fei Chong, … , Constantine S. Mitsiades, Matthew S. Davids
Stephen Jun Fei Chong, … , Constantine S. Mitsiades, Matthew S. Davids
Published September 26, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI170169.
View: Text | PDF

Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies

  • Text
  • PDF
Abstract

The BCL-2 inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B-cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL-2 mutations have been described, this likely only explains a subset of resistant cases. Using two complementary functional precision medicine techniques -- BH3-profiling and high throughput-kinase activity mapping -- we found that hyperphosphorylation of BCL-2 family proteins, including anti-apoptotic MCL-1 and BCL-2 and pro-apoptotic BAD and BAX, underlies functional mechanisms of both intrinsic and acquired resistance of venetoclax in CLL and DLBCL. Additionally, we provide evidence that anti-apoptotic BCL-2 family protein phosphorylation alters the apoptotic protein interactome, thereby changing the profile of functional dependence on these pro-survival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs re-wired these dependences, thus restoring sensitivity to venetoclax in a panel of venetoclax resistant lymphoid cell lines, resistant mouse model, and paired patient samples pre-venetoclax and at time of progression.

Authors

Stephen Jun Fei Chong, Fen Zhu, Olga Dashevsky, Rin Mizuno, Jolin X.H. Lai, Liam Hackett, Christine E. Ryan, Mary C. Collins, J. Bryan Iorgulescu, Romain Guièze, Johany Penailillo, Ruben Carrasco, Yeonjoo C. Hwang, Denise P. Muñoz, Mehdi Bouhaddou, Yaw Chyn Lim, Catherine J. Wu, John N. Allan, Richard R. Furman, Boon Cher Goh, Shazib Pervaiz, Jean-Philippe Coppé, Constantine S. Mitsiades, Matthew S. Davids

×

Hypoxic erythrocytes mediate cardioprotection through activation of soluble guanylate cyclase and release of cyclic GMP
Jiangning Yang, … , Jon O. Lundberg, John Pernow
Jiangning Yang, … , Jon O. Lundberg, John Pernow
Published September 1, 2023
Citation Information: J Clin Invest. 2023;133(17):e167693. https://doi.org/10.1172/JCI167693.
View: Text | PDF

Hypoxic erythrocytes mediate cardioprotection through activation of soluble guanylate cyclase and release of cyclic GMP

  • Text
  • PDF
Abstract

Red blood cells (RBCs) mediate cardioprotection via nitric oxide–like bioactivity, but the signaling and the identity of any mediator released by the RBCs remains unknown. We investigated whether RBCs exposed to hypoxia release a cardioprotective mediator and explored the nature of this mediator. Perfusion of isolated hearts subjected to ischemia-reperfusion with extracellular supernatant from mouse RBCs exposed to hypoxia resulted in improved postischemic cardiac function and reduced infarct size. Hypoxia increased extracellular export of cyclic guanosine monophosphate (cGMP) from mouse RBCs, and exogenous cGMP mimicked the cardioprotection induced by the supernatant. The protection induced by hypoxic RBCs was dependent on RBC-soluble guanylate cyclase and cGMP transport and was sensitive to phosphodiesterase 5 and activated cardiomyocyte protein kinase G. Oral administration of nitrate to mice to increase nitric oxide bioactivity further enhanced the cardioprotective effect of hypoxic RBCs. In a placebo-controlled clinical trial, a clear cardioprotective, soluble guanylate cyclase–dependent effect was induced by RBCs collected from patients randomized to 5 weeks nitrate-rich diet. It is concluded that RBCs generate and export cGMP as a response to hypoxia, mediating cardioprotection via a paracrine effect. This effect can be further augmented by a simple dietary intervention, suggesting preventive and therapeutic opportunities in ischemic heart disease.

Authors

Jiangning Yang, Michaela L. Sundqvist, Xiaowei Zheng, Tong Jiao, Aida Collado, Yahor Tratsiakovich, Ali Mahdi, John Tengbom, Evanthia Mergia, Sergiu-Bogdan Catrina, Zhichao Zhou, Mattias Carlström, Takaaki Akaike, Miriam M. Cortese-Krott, Eddie Weitzberg, Jon O. Lundberg, John Pernow

×

RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition
Amy C. Fan, … , Purvesh Khatri, Ravindra Majeti
Amy C. Fan, … , Purvesh Khatri, Ravindra Majeti
Published August 15, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI167053.
View: Text | PDF

RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition

  • Text
  • PDF
Abstract

Disease-initiating mutations in the transcription factor RUNX1 occur as germline and somatic events that cause leukemias with particularly poor prognosis. However, the role of RUNX1 in leukemogenesis is not fully understood and effective therapies for RUNX1-mutant leukemias remain elusive. Here, we use primary patient samples and a RUNX1 knockout model in primary human hematopoietic cells to investigate how RUNX1 loss contributes to leukemic progression and to identify targetable vulnerabilities. Surprisingly, we found that RUNX1 loss decreased proliferative capacity and stem cell function. However, RUNX1-deficient cells selectively upregulated the interleukin-3 (IL-3) receptor. Exposure to IL-3, but not other JAK/STAT cytokines, rescued RUNX1 KO proliferative and competitive defects. Further, we demonstrated that RUNX1 loss repressed JAK/STAT signaling and rendered RUNX1-deficient cells sensitive to JAK inhibitors. Our study identifies a dependency of RUNX1-mutant leukemias on IL-3/JAK/STAT signaling, which may enable these aggressive blood cancers to be targeted with existing agents.

Authors

Amy C. Fan, Yusuke Nakauchi, Lawrence Bai, Armon Azizi, Kevin A. Nuno, Feifei Zhao, Thomas Köhnke, Daiki Karigane, David Cruz-Hernandez, Andreas Reinisch, Purvesh Khatri, Ravindra Majeti

×

Regulation of antigen-specific T cell infiltration and spatial architecture in multiple myeloma and premalignancy
M. Hope Robinson, … , Kavita M. Dhodapkar, Madhav V. Dhodapkar
M. Hope Robinson, … , Kavita M. Dhodapkar, Madhav V. Dhodapkar
Published August 1, 2023
Citation Information: J Clin Invest. 2023;133(15):e167629. https://doi.org/10.1172/JCI167629.
View: Text | PDF

Regulation of antigen-specific T cell infiltration and spatial architecture in multiple myeloma and premalignancy

  • Text
  • PDF
Abstract

Entry of antigen-specific T cells into human tumors is critical for immunotherapy, but the underlying mechanisms are poorly understood. Here, we combined high-dimensional spatial analyses with in vitro and in vivo modeling to study the mechanisms underlying immune infiltration in human multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). Clustered tumor growth was a feature of MM but not MGUS biopsies, and this growth pattern was reproduced in humanized mouse models. MM biopsies exhibited intralesional as well as spatial heterogeneity, with coexistence of T cell–rich and T cell–sparse regions and the presence of areas of T cell exclusion. In vitro studies demonstrated that T cell entry into MM clusters was regulated by agonistic signals and CD2-CD58 interactions. Upon adoptive transfer, antigen-specific T cells localized to the tumor site but required in situ DC–mediated antigen presentation for tumor entry. C-type lectin domain family 9 member A–positive (CLEC9A+) DCs appeared to mark portals of entry for gradients of T cell infiltration in MM biopsies, and their proximity to T cell factor 1–positive (TCF1+) T cells correlated with disease state and risk status. These data illustrate a role for tumor-associated DCs and in situ activation in promoting the infiltration of antigen-specific T cells in MM and provide insights into spatial alterations in tumor/immune cells with malignant evolution.

Authors

M. Hope Robinson, Nancy Y. Villa, David L. Jaye, Ajay K. Nooka, Alyssa Duffy, Samuel S. McCachren, Julia Manalo, Jeffrey M. Switchenko, Sierra Barnes, Sayalee Potdar, Maryam I. Azeem, Ava A. Horvat, Vaunita C. Parihar, Jingjing Gong, Yan Liang, Geoffrey H. Smith, Vikas A. Gupta, Lawrence H. Boise, Jonathan L. Kaufman, Craig C. Hofmeister, Nisha S. Joseph, Sagar Lonial, Kavita M. Dhodapkar, Madhav V. Dhodapkar

×

Foxm1 haploinsufficiency drives clonal hematopoiesis and promotes a stress-related transition to hematologic malignancy in mice
Chunjie Yu, … , Yong Huang, Zhijian Qian
Chunjie Yu, … , Yong Huang, Zhijian Qian
Published August 1, 2023
Citation Information: J Clin Invest. 2023;133(15):e163911. https://doi.org/10.1172/JCI163911.
View: Text | PDF

Foxm1 haploinsufficiency drives clonal hematopoiesis and promotes a stress-related transition to hematologic malignancy in mice

  • Text
  • PDF
Abstract

Clonal hematopoiesis plays a critical role in the initiation and development of hematologic malignancies. In patients with del(5q) myelodysplastic syndrome (MDS), the transcription factor FOXM1 is frequently downregulated in CD34+ cells. In this study, we demonstrated that Foxm1 haploinsufficiency disturbed normal hematopoiesis and conferred a competitive repopulation advantage for a short period. However, it impaired the long-term self-renewal capacity of hematopoietic stem cells, recapitulating the phenotypes of abnormal hematopoietic stem cells observed in patients with MDS. Moreover, heterozygous inactivation of Foxm1 led to an increase in DNA damage in hematopoietic stem/progenitor cells (HSPCs). Foxm1 haploinsufficiency induced hematopoietic dysplasia in a mouse model with LPS-induced chronic inflammation and accelerated AML-ETO9a–mediated leukemogenesis. We have also identified Parp1, an important enzyme that responds to various types of DNA damage, as a target of Foxm1. Foxm1 haploinsufficiency decreased the ability of HSPCs to efficiently repair DNA damage by downregulating Parp1 expression. Our findings suggest that the downregulation of the Foxm1-Parp1 molecular axis may promote clonal hematopoiesis and reduce genome stability, contributing to del(5q) MDS pathogenesis.

Authors

Chunjie Yu, Yue Sheng, Fang Yu, Hongyu Ni, Alan Qiu, Yong Huang, Zhijian Qian

×
  • ← Previous
  • 1
  • 2
  • 3
  • …
  • 33
  • 34
  • Next →
Teasing apart active site contributions
Junsong Zhou, Yi Wu, and colleagues reveal that the C-terminal redox-active site of protein disulfide isomerase is essential for coagulation…
Published November 3, 2015
Scientific Show StopperHematology

PRMT5 keeps hematopoietic cells renewing
Fan Liu and colleagues demonstrate that the type II arginine methyltransferase PRMT5 is an important regulator of hematopoietic cell maintenance…
Published August 10, 2015
Scientific Show StopperHematology

Moving toward donor-independent platelets
Ji-Yoon Noh and colleagues use a fine-tuned approach to generate platelet-producing megakaryocyte-erythroid progenitors from murine embryonic stem cells…
Published May 11, 2015
Scientific Show StopperHematology

A family affair
Vijay Sankaran and colleagues demonstrate that a mutation in the X-chromosomal gene encoding aminolevulinic acid synthase underlies disease in a family with macrocytic anemia…
Published February 23, 2015
Scientific Show StopperHematology
Advertisement

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts