Browsing by Author "Broxmeyer, Hal E."

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    6: Effect of CD26 on Cord Blood, and Other Means to Enhance Engraftment of Hematopoietic Stem Cells
    (E6325, 2007-11-01) Broxmeyer, Hal E.; Medicine, School of Medicine
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    A target discovery pipeline identified ILT3 as a target for immunotherapy of multiple myeloma
    (Elsevier, 2023) Di Meo, Francesco; Iyer, Anjushree; Akama, Keith; Cheng, Rujin; Yu, Christina; Cesarano, Annamaria; Kurihara, Noriyoshi; Tenshin, Hirofumi; Aljoufi, Arafat; Marino, Silvia; Soni, Rajesh K.; Roda, Julie; Sissons, James; Vu, Ly P.; Guzman, Monica; Huang, Kun; Laskowski, Tamara; Broxmeyer, Hal E.; Roodman, David G.; Perna, Fabiana; Medicine, School of Medicine
    Multiple myeloma (MM) is an incurable malignancy of plasma cells. To identify targets for MM immunotherapy, we develop an integrated pipeline based on mass spectrometry analysis of seven MM cell lines and RNA sequencing (RNA-seq) from 900+ patients. Starting from 4,000+ candidates, we identify the most highly expressed cell surface proteins. We annotate candidate protein expression in many healthy tissues and validate the expression of promising targets in 30+ patient samples with relapsed/refractory MM, as well as in primary healthy hematopoietic stem cells and T cells by flow cytometry. Six candidates (ILT3, SEMA4A, CCR1, LRRC8D, FCRL3, IL12RB1) and B cell maturation antigen (BCMA) present the most favorable profile in malignant and healthy cells. We develop a bispecific T cell engager targeting ILT3 that shows potent killing effects in vitro and decreased tumor burden and prolonged mice survival in vivo, suggesting therapeutic relevance. Our study uncovers MM-associated antigens that hold great promise for immune-based therapies of MM.
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    Activation of OCT4 enhances ex vivo expansion of human cord blood hematopoietic stem and progenitor cells by regulating HOXB4 expression
    (SpringerNature, 2016-01) Huang, Xinxin; Lee, Man-Ryul; Cooper, Scott; Hangoc, Giao; Hong, Ki-Sung; Chung, Hyung-Min; Broxmeyer, Hal E.; Department of Microbiology & Immunology, IU School of Medicine
    Although hematopoietic stem cells (HSC) are the best characterized and the most clinically used adult stem cells, efforts are still needed to understand how to best ex vivo expand these cells. Here we present our unexpected finding that OCT4 is involved in the enhancement of cytokine-induced expansion capabilities of human cord blood (CB) HSC. Activation of OCT4 by Oct4-activating compound 1 (OAC1) in CB CD34(+) cells enhanced ex vivo expansion of HSC, as determined by a rigorously defined set of markers for human HSC, and in vivo short-term and long-term repopulating ability in NSG mice. Limiting dilution analysis revealed that OAC1 treatment resulted in 3.5-fold increase in the number of SCID repopulating cells (SRCs) compared with that in day 0 uncultured CD34(+) cells and 6.3-fold increase compared with that in cells treated with control vehicle. Hematopoietic progenitor cells, as assessed by in vitro colony formation, were also enhanced. Furthermore, we showed that OAC1 treatment led to OCT4-mediated upregulation of HOXB4. Consistently, siRNA-mediated knockdown of HOXB4 expression suppressed effects of OAC1 on ex vivo expansion of HSC. Our study has identified the OCT4-HOXB4 axis in ex vivo expansion of human CB HSC.
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    ADGRG1 enriches for functional human hematopoietic stem cells following ex vivo expansion-induced mitochondrial oxidative stress
    (The American Society for Clinical Investigation, 2021) Chen, Yandan; Fang, Shuyi; Ding, Qingwei; Jiang, Rongzhen; He, Jiefeng; Wang, Qin; Jin, Yuting; Huang, Xinxin; Liu, Sheng; Capitano, Maegan L.; Trinh, Thao; Teng, Yincheng; Meng, Qingyou; Wan, Jun; Broxmeyer, Hal E.; Guo, Bin; BioHealth Informatics, School of Informatics and Computing
    The heterogeneity of human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) under stress conditions such as ex vivo expansion is poorly understood. Here, we report that the frequencies of SCID-repopulating cells were greatly decreased in cord blood (CB) CD34+ HSCs and HPCs upon ex vivo culturing. Transcriptomic analysis and metabolic profiling demonstrated that mitochondrial oxidative stress of human CB HSCs and HPCs notably increased, along with loss of stemness. Limiting dilution analysis revealed that functional human HSCs were enriched in cell populations with low levels of mitochondrial ROS (mitoROS) during ex vivo culturing. Using single-cell RNA-Seq analysis of the mitoROS low cell population, we demonstrated that functional HSCs were substantially enriched in the adhesion GPCR G1-positive (ADGRG1+) population of CD34+CD133+ CB cells upon ex vivo expansion stress. Gene set enrichment analysis revealed that HSC signature genes including MSI2 and MLLT3 were enriched in CD34+CD133+ADGRG1+ CB HSCs. Our study reveals that ADGRG1 enriches for functional human HSCs under oxidative stress during ex vivo culturing, which can be a reliable target for drug screening of agonists of HSC expansion.
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    Age-related decline in LEPR+ hematopoietic stem cell function
    (Springer Nature, 2023) Trinh, Thao; Ropa, James; Cooper, Scott; Aljoufi, Arafat; Sinn, Anthony; Capitano, Maegan; Broxmeyer, Hal E.; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
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    All in for nuclear PFKP–induced CXCR4 metastasis: a T cell acute lymphoblastic leukemia prognostic marker
    (The American Society for Clinical Investigation, 2021) Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Phosphofructokinase 1 (PFK1) is expressed in T cell acute lymphoblastic leukemia (T-ALL), where its upregulation is linked with cancer progression. While PFK1 functions in the glycolysis pathway within the cytoplasm, it is also present in the nucleus where it regulates gene transcription. In this issue of the JCI, Xueliang Gao, Shenghui Qin, et al. focus their mechanism-based investigation on the nucleocytoplasmic shuttling aspect of the PFK1 platelet isoform, PFKP. Functional nuclear export and localization sequences stimulated CXC chemokine receptor type 4 (CXCR4) expression to promote T-ALL invasion that involved cyclin D3/CDK6, c-Myc, and importin-9. Since the presence of nuclear PFKP is associated with poor survival in T-ALL, nuclear PFKP-induced CXCR4 expression might serve as a prognostic marker for T-ALL. More promising, though, are the mechanistic insights suggesting that approaches to dampening metastatic migration may have application to benefit patients with T-ALL.
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    Altered Hematopoiesis, Behavior, and Sexual Function in μ Opioid Receptor–deficient Mice
    (Rockefeller University Press, 1997) Tian, Mingting; Broxmeyer, Hal E.; Fan, Yi; Lai, Zhennan; Zhang, Shengwen; Aronica, Susan; Cooper, Scott; Bigsby, Robert M.; Steinmetz, Rosemary; Engle, Sandra J.; Mestek, Anton; Pollock, Jonathan D.; Lehman, Michael N.; Jansen, Heiko T.; Ying, Moyin; Stambrook, Peter J.; Tischfield, Jay A.; Yu, Lei; Microbiology and Immunology, School of Medicine
    The mu opioid receptor is thought to be the cellular target of opioid narcotics such as morphine and heroin, mediating their effects in both pain relief and euphoria. Its involvement is also implicated in a range of diverse biological processes. Using a mouse model in which the receptor gene was disrupted by targeted homologous recombination, we explored the involvement of this receptor in a number of physiological functions. Mice homozygous for the disrupted gene developed normally, but their motor function was altered. Drug-naive homozygotes displayed reduced locomotor activity, and morphine did not induce changes in locomotor activity observed in wild-type mice. Unexpectedly, lack of a functional receptor resulted in changes in both the host defense system and the reproductive system. We observed increased proliferation of granulocyte-macrophage, erythroid, and multipotential progenitor cells in both bone marrow and spleen, indicating a link between hematopoiesis and the opioid system, both of which are stress-responsive systems. Unexpected changes in sexual function in male homozygotes were also observed, as shown by reduced mating activity, a decrease in sperm count and motility, and smaller litter size. Taken together, these results suggest a novel role of the mu opioid receptor in hematopoiesis and reproductive physiology, in addition to its known involvement in pain relief.
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    Ames hypopituitary dwarf mice demonstrate imbalanced myelopoiesis between bone marrow and spleen
    (Elsevier, 2015-06) Capitano, Maegan L.; Chitteti, Brahmananda R.; Cooper, Scott; Srour, Edward F.; Bartke, Andrzej; Broxmeyer, Hal E.; Department of Microbiology & Immunology, IU School of Medicine
    Ames hypopituitary dwarf mice are deficient in growth hormone, thyroid-stimulating hormone, and prolactin. The phenotype of these mice demonstrates irregularities in the immune system with skewing of the normal cytokine milieu towards a more anti-inflammatory environment. However, the hematopoietic stem and progenitor cell composition of the bone marrow (BM) and spleen in Ames dwarf mice has not been well characterized. We found that there was a significant decrease in overall cell count when comparing the BM and spleen of 4-5 month old dwarf mice to their littermate controls. Upon adjusting counts to differences in body weight between the dwarf and control mice, the number of granulocyte-macrophage progenitors, confirmed by immunophenotyping and colony-formation assay was increased in the BM. In contrast, the numbers of all myeloid progenitor populations in the spleen were greatly reduced, as confirmed by colony-formation assays. This suggests that there is a shift of myelopoiesis from the spleen to the BM of Ames dwarf mice; however, this shift does not appear to involve erythropoiesis. The reasons for this unusual shift in spleen to marrow hematopoiesis in Ames dwarf mice are yet to be determined but may relate to the decreased hormone levels in these mice.
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    Antagonism of PPARγ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis
    (Nature Publishing group, 2018-03) Guo, Bin; Huang, Xinxin; Lee, Man Ryul; Lee, Sang A; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Hematopoietic stem cells (HSCs) quiescently reside in bone marrow niches and have the capacity to self-renew or differentiate to form all blood cells throughout the lifespan of an animal–. Allogeneic HSC transplantation is a life-saving treatment for malignant and non-malignant disorders,. HSCs isolated from umbilical cord blood (CB) are used for hematopoietic cell transplantation (HCT)–, but due to limited numbers of HSCs in single units of umbilical CB, a number of methods have been proposed for ex vivo expansion of human HSCs,,. We show here that antagonism of the nuclear hormone receptor PPARγ promotes ex vivo expansion of phenotypically and functionally-defined subsets of human CB HSCs and hematopoietic progenitor cells (HSPCs). PPARγ antagonism in CB HSPCs strongly downregulated expression of several differentiation associated genes, as well as fructose 1, 6-bisphosphatase (FBP1), a negative regulator of glycolysis, and enhanced glycolysis without compromising mitochondrial metabolism. The expansion of CB HSPCs by PPARγ antagonism was completely suppressed by removal of glucose or inhibition of glycolysis. Moreover, knockdown of FBP1 expression promoted glycolysis and ex vivo expansion of long-term repopulating CB HSPCs, whereas overexpression of FBP1 suppressed the expansion of CB HSPCs induced by PPARγ antagonism. Our study suggests the possibility for a new and simple means for metabolic reprogramming of CB HSPCs to improve the efficacy of HCT.
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    Associated guilt: radiation/bystanders
    (American Society of Hematology, 2021-06-17) Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Radiation-induced bystander effects (RIBEs) is a neglected, but crucial, area of radiation response. In this issued of Blood, Hu et al have provided important new information and mechanistic insights into RIBE-impairment of hematopoietic stem (HSC) and progenitor (HPC) cells in hematopoietic cell transplantation (HCT), with implications for the mitigation of RIBEs.