Publications by authors named "Laura M Calvi"

53 Publications

Improved in vivo Experimental Screening Identifies an Anabolic Analog of 1,25 Dihydroxyvitamin D3 With Minimal Bone Resorption Activity.

Authors:
Laura M Calvi

J Bone Miner Res 2020 04 6;35(4):621-622. Epub 2020 Jan 6.

Department of Medicine and Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.

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http://dx.doi.org/10.1002/jbmr.3933DOI Listing
April 2020

What is the role of the microenvironment in MDS?

Best Pract Res Clin Haematol 2019 12 28;32(4):101113. Epub 2019 Oct 28.

University of Rochester School of Medicine, Wilmot Cancer Institute, 601 Elmwood Avenue, Box 794, Rochester, NY, 14642, USA.

Treating myelodysplastic syndromes (MDS) remains challenging. Hematopoiesis occurs within a heterogeneous, complex and dynamic microenvironment, and a multiplicity of mutations in hematopoietic stem and progenitor cells (HSPCs) lead to MDS. But is there a role for the microenvironment? Here we review experimental and conceptual arguments that support a role for the microenvironment, provide evidence for the disruption of the microenvironment in MDS, and explore microenvironmental signals that may provide a targetable and conserved vulnerability in MDS that transcend genetic heterogeneity.
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http://dx.doi.org/10.1016/j.beha.2019.101113DOI Listing
December 2019

Bone marrow mesenchymal stromal cells from acute myelogenous leukemia patients demonstrate adipogenic differentiation propensity with implications for leukemia cell support.

Leukemia 2020 02 6;34(2):391-403. Epub 2019 Sep 6.

Department of Medicine, Hematology/Oncology, University of Rochester, Rochester, NY, USA.

Bone marrow mesenchymal stromal cells (MSCs) constitute one of the important components of the hematopoietic microenvironmental niche. In vivo studies have shown that depletion of marrow MSCs resulted in reduction of hematopoietic stem cell content, and there is in vitro evidence that marrow MSCs are able to support leukemia progenitor cell proliferation and survival and provide resistance to cytotoxic therapies. How MSCs from leukemia marrow differ from normal counterparts and how they are influenced by the presence of leukemia stem and progenitor cells are still incompletely understood. In this work, we compared normal donor (ND) and acute myelogenous leukemia (AML) derived MSCs and found that AML-MSCs had increased adipogenic potential with improved ability to support survival of leukemia progenitor cells. To identify underlying changes, RNA-Seq analysis was performed. Gene ontology and pathway analysis revealed adipogenesis to be among the set of altered biological pathways dysregulated in AML-MSCs as compared with ND-MSCs. Expression of both SOX9 and EGR2 was decreased in AML-MSCs as compared with ND-MSCs. Increasing expression of SOX9 decreased adipogenic potential of AML-MSCs and decreased their ability to support AML progenitor cells. These findings suggest that AML-MSCs possess adipogenic potential which may enhance support of leukemia progenitor cells.
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http://dx.doi.org/10.1038/s41375-019-0568-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214245PMC
February 2020

Acute and late effects of combined internal and external radiation exposures on the hematopoietic system.

Int J Radiat Biol 2019 11 30;95(11):1447-1461. Epub 2019 Jul 30.

Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA.

Incidents, such as nuclear facility accidents and the release of a 'dirty bomb', might result in not only external irradiation of personnel, but additional internal exposures through concomitant inhalation and/or ingestion of radioactive particulates. The purpose of this study was to define the impact of such a combination of radiation injuries on the hematopoietic niche. To assess changes in the murine hematopoietic system, we used a combined exposure of total body irradiation (TBI, 6 Gy) followed immediately by an internal (intraperitoneal) administration of 100 Ci of soluble Cs. We then evaluated acute survival in combined versus single modality exposure groups, as well as assessing hematopoietic function at 12 and 26 week time points. Acutely, the combination of external and internal exposures led to an unexpected delay in excretion of Cs, increasing the absorbed dose in the combined exposure group and leading to mortality from an acute hematopoietic syndrome. At 12 weeks, all exposure paradigms resulted in decreased numbers of phenotypic hematopoietic stem cells (HSCs), particularly the short-term HSCs (ST-HSC); long-term HSCs (LT-HSC) were depleted only in the internal and combined exposure groups. At 26 weeks, there was significant anemia in both the TBI alone and combined exposure groups. There were decreased numbers in both the LT- and ST-HSCs and decreased functionality, as measured by competitive repopulation, was seen in all radiation groups, with the greatest effects seen in the internal and combined exposure groups. Our data indicate that a combined injury of sublethal external irradiation with internal contamination induces significant and persistent changes in the hematopoietic system, as may have been predicted from the literature and our own group's findings. However, a novel observation was that the combined exposure led to an alteration in the excretion kinetics of the internal contamination, increasing the acute effects beyond those anticipated. As a result, we believe that a combined exposure poses a unique challenge to the medical community during both the acute and, possibly, delayed recovery stages.
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http://dx.doi.org/10.1080/09553002.2019.1644932DOI Listing
November 2019

A Novel Strategy for Repairing Multiple Myeloma Bone Lesions: Lessons From Murine Models.

J Bone Miner Res 2019 05 9;34(5):781-782. Epub 2019 May 9.

Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.

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http://dx.doi.org/10.1002/jbmr.3723DOI Listing
May 2019

Flaming and fanning: The Spectrum of inflammatory influences in myelodysplastic syndromes.

Blood Rev 2019 07 18;36:57-69. Epub 2019 Apr 18.

Division of Hematology/Oncology, Department of Medicine, James P Wilmot Cancer Institute, USA. Electronic address:

The myelodysplastic syndromes (MDS) represent neoplasms derived from the expansion of mutated clonal hematopoietic cells which often demonstrate aberrant differentiation potential with resultant cytopenias and a propensity to evolve into acute myelogenous leukemia. While multiple mutations have been identified which may serve as drivers of the MDS clone, there is accumulating evidence that MDS clones and subclones are subject to modulation by the marrow microenvironment and its inflammatory milieu. There is also a strong link between autoimmune disorders and MDS. In this review, we examine the role of inflammatory cytokines, toll like receptors, pyroptosis, stromal cells, and cellular inflammatory mediators in MDS initiation, propagation, and progression. These contributions in a background of mutational, epigenetic, and aging changes in the marrow are also reviewed. Such inflammatory mediators may be subject to therapeutic agents which will enhance suppression of the MDS clone with potential to improve therapeutic outcomes in this disease which is usually incurable in aged patients not eligible for stem cell transplantation.
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http://dx.doi.org/10.1016/j.blre.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711159PMC
July 2019

Aged marrow macrophages expand platelet-biased hematopoietic stem cells via Interleukin1B.

JCI Insight 2019 04 18;5. Epub 2019 Apr 18.

Department of Medicine.

The bone marrow microenvironment (BMME) contributes to the regulation of hematopoietic stem cell (HSC) function, though its role in age-associated lineage skewing is poorly understood. Here we show that dysfunction of aged marrow macrophages (Mφs) directs HSC platelet-bias. Mφs from the marrow of aged mice and humans exhibited an activated phenotype, with increased expression of inflammatory signals. Aged marrow Mφs also displayed decreased phagocytic function. Senescent neutrophils, typically cleared by marrow Mφs, were markedly increased in aged mice, consistent with functional defects in Mφ phagocytosis and efferocytosis. In aged mice, Interleukin 1B (IL1B) was elevated in the bone marrow and caspase 1 activity, which can process pro-IL1B, was increased in marrow Mφs and neutrophils. Mechanistically, IL1B signaling was necessary and sufficient to induce a platelet bias in HSCs. In young mice, depletion of phagocytic cell populations or loss of the efferocytic receptor Axl expanded platelet-biased HSCs. Our data support a model wherein increased inflammatory signals and decreased phagocytic function of aged marrow Mφs induce the acquisition of platelet bias in aged HSCs. This work highlights the instructive role of Mφs and IL1B in the age-associated lineage-skewing of HSCs, and reveals the therapeutic potential of their manipulation as antigeronic targets.
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http://dx.doi.org/10.1172/jci.insight.124213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542605PMC
April 2019

EVI1 overexpression reprograms hematopoiesis via upregulation of Spi1 transcription.

Nat Commun 2018 10 12;9(1):4239. Epub 2018 Oct 12.

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA.

Inv(3q26) and t(3:3)(q21;q26) are specific to poor-prognosis myeloid malignancies, and result in marked overexpression of EVI1, a zinc-finger transcription factor and myeloid-specific oncoprotein. Despite extensive study, the mechanism by which EVI1 contributes to myeloid malignancy remains unclear. Here we describe a new mouse model that mimics the transcriptional effects of 3q26 rearrangement. We show that EVI1 overexpression causes global distortion of hematopoiesis, with suppression of erythropoiesis and lymphopoiesis, and marked premalignant expansion of myelopoiesis that eventually results in leukemic transformation. We show that myeloid skewing is dependent on DNA binding by EVI1, which upregulates Spi1, encoding master myeloid regulator PU.1. We show that EVI1 binds to the -14 kb upstream regulatory element (-14kbURE) at Spi1; knockdown of Spi1 dampens the myeloid skewing. Furthermore, deletion of the -14kbURE at Spi1 abrogates the effects of EVI1 on hematopoietic stem cells. These findings support a novel mechanism of leukemogenesis through EVI1 overexpression.
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http://dx.doi.org/10.1038/s41467-018-06208-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185954PMC
October 2018

The Chemokine CCL3 Regulates Myeloid Differentiation and Hematopoietic Stem Cell Numbers.

Sci Rep 2018 10 2;8(1):14691. Epub 2018 Oct 2.

Department of Medicine Hematology/Oncology Division University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.

The chemokine CCL3 is frequently overexpressed in malignancies and overexpression leads to microenvironmental dysfunction. In murine models of chronic myelogenous leukemia (CML), CCL3 is critical for the maintenance of a leukemia stem cell population, and leukemia progression. With CCL3 implicated as a potentially viable therapeutic target, it is important to carefully characterize its role in normal hematopoietic homeostasis. CCL3 mice were used to evaluate the role of CCL3 in regulating hematopoietic stem and progenitor cell (HSPC) populations. CCL3 mice had loss of mature myeloid populations, while myeloid progenitors and HSPCs were increased, and microenvironmental populations were unchanged. These data show that CCL3 promotes myeloid lineage differentiation and the size of the HSPC pool independent of the supportive bone marrow microenvironment. Our results demonstrate a previously unrecognized role of CCL3 in the maintenance of homeostatic hematopoiesis that should be evaluated when targeting CCL3 signaling for the treatment of hematologic malignancy.
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http://dx.doi.org/10.1038/s41598-018-32978-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168534PMC
October 2018

Impact of aging on bone, marrow and their interactions.

Bone 2019 02 17;119:1-7. Epub 2018 Jul 17.

University of Rochester Medical Center, Rochester, NY, United States of America. Electronic address:

Hematopoiesis in land dwelling vertebrates and marine mammals occurs within the bone marrow, continually providing mature progeny over the course of an organism's lifetime. This conserved dependency highlights the critical relationship between these two organs, yet the skeletal and hematopoietic systems are often thought of as separate. In fact, data are beginning to show that skeletal disease pathogenesis influences hematopoiesis and viceversa, offering novel opportunities to approach disease affecting bone and blood. With a growing global population of aged individuals, interest has focused on cell autonomous changes in hematopoietic and skeletal systems that result in dysfunction. The purpose of this review is to summarize the literature on aging effects in both fields, and provide critical examples of organ cross-talk in the aging process.
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http://dx.doi.org/10.1016/j.bone.2018.07.012DOI Listing
February 2019

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression.

Exp Hematol 2017 11 18;55:3-18. Epub 2017 Aug 18.

Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY. Electronic address:

Myelodysplastic syndromes (MDSs) are clonal disorders of hematopoietic stem and progenitor cells and represent the most common cause of acquired marrow failure. Hallmarked by ineffective hematopoiesis, dysplastic marrow, and risk of transformation to acute leukemia, MDS remains a poorly treated disease. Although identification of hematopoietic aberrations in human MDS has contributed significantly to our understanding of MDS pathogenesis, evidence now identify the bone marrow microenvironment (BMME) as another key contributor to disease initiation and progression. With improved understanding of the BMME, we are beginning to refine the role of the hematopoietic niche in MDS. Despite genetic diversity in MDS, interaction between MDS and the BMME appears to be a common disease feature and therefore represents an appealing therapeutic target. Further understanding of the interdependent relationship between MDS and its niche is needed to delineate the mechanisms underlying hematopoietic failure and how the microenvironment can be targeted clinically. This review provides an overview of data from human MDS and murine models supporting a role for BMME dysfunction at several steps of disease pathogenesis. Although no models or human studies so far have combined all of these findings, we review current data identifying BMME involvement in each step of MDS pathogenesis organized to reflect the chronology of BMME contribution as the normal hematopoietic system becomes myelodysplastic and MDS progresses to marrow failure and transformation. Although microenvironmental heterogeneity and dysfunction certainly add complexity to this syndrome, data are already demonstrating that targeting microenvironmental signals may represent novel therapeutic strategies for MDS treatment.
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http://dx.doi.org/10.1016/j.exphem.2017.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737956PMC
November 2017

The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool.

J Bone Miner Res 2017 Jun 9;32(6):1320-1331. Epub 2017 Mar 9.

Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.

Notch signaling is critical for osteoblastic differentiation; however, the specific contribution of individual Notch ligands is unknown. Parathyroid hormone (PTH) regulates the Notch ligand Jagged1 in osteoblastic cells. To determine if osteolineage Jagged1 contributes to bone homeostasis, selective deletion of Jagged1 in osteolineage cells was achieved through the presence of Prx1 promoter-driven Cre recombinase expression, targeting mesenchymal stem cells (MSCs) and their progeny (PJag1 mice). PJag1 mice were viable and fertile and did not exhibit any skeletal abnormalities at 2 weeks of age. At 2 months of age, however, PJag1 mice had increased trabecular bone mass compared to wild-type (WT) littermates. Dynamic histomorphometric analysis showed increased osteoblastic activity and increased mineral apposition rate. Immunohistochemical analysis showed increased numbers of osteocalcin-positive mature osteoblasts in PJag1 mice. Also increased phenotypically defined Lin /CD45 /CD31 /Sca1 /CD51 osteoblastic cells were measured by flow cytometric analysis. Surprisingly, phenotypically defined Lin /CD45 /CD31 /Sca1 /CD51 MSCs were unchanged in PJag1 mice as measured by flow cytometric analysis. However, functional osteoprogenitor (OP) cell frequency, measured by Von Kossa colony formation, was decreased, suggesting that osteolineage Jagged1 contributes to maintenance of the OP pool. The trabecular bone increases were not due to osteoclastic defects, because PJag1 mice had increased bone resorption. Because PTH increases osteoblastic Jagged1, we sought to understand if osteolineage Jagged1 modulates PTH-mediated bone anabolism. Intermittent PTH treatment resulted in a significantly greater increase in BV/TV in PJag1 hind limbs compared to WT. These findings demonstrate a critical role of osteolineage Jagged1 in bone homeostasis, where Jagged1 maintains the transition of OP to maturing osteoblasts. This novel role of Jagged1 not only identifies a regulatory loop maintaining appropriate populations of osteolineage cells, but also provides a novel approach to increase trabecular bone mass, particularly in combination with PTH, through modulation of Jagged1. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466455PMC
June 2017

The aging hematopoietic stem cell niche: Phenotypic and functional changes and mechanisms that contribute to hematopoietic aging.

Semin Hematol 2017 01 19;54(1):25-32. Epub 2016 Oct 19.

Endocrine Metabolism Division, University of Rochester School of Medicine and Dentistry, Rochester NY; Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester NY. Electronic address:

The hematopoietic system has the remarkable ability to provide a lifelong supply of mature cells that make up the entire blood and immune system. However, similar to other adult stem cell niches, the hematopoietic system is vulnerable to the detrimental effects of aging. This is a substantial health concern as the trend for population aging continues to increase. Identifying mechanisms that underlie hematopoietic aging is vital for understanding hematopoietic-related diseases. In this review, we first discuss the cellular hierarchy of the hematopoietic system and the components that make up the surrounding hematopoietic niche. We then provide an overview of the major phenotypes associated with hematopoietic aging and discuss recent research investigating cell-intrinsic and cell-extrinsic mechanisms of hematopoietic stem cell (HSCs) aging. We end by discussing the exciting new concept of possibly reversing the HSC aging process along with outstanding questions that remain to be answered.
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http://dx.doi.org/10.1053/j.seminhematol.2016.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244432PMC
January 2017

Late presentation of acromegaly in medically controlled prolactinoma patients.

Endocrinol Diabetes Metab Case Rep 2016 17;2016. Epub 2016 Oct 17.

Department of Endocrinology , Diabetes and Metabolism.

Co-secretion of growth hormone (GH) and prolactin (PRL) from a single pituitary adenoma is common. In fact, up to 25% of patients with acromegaly may have PRL co-secretion. The prevalence of acromegaly among patients with a newly diagnosed prolactinoma is unknown. Given the possibility of mixed GH and PRL co-secretion, the current recommendation is to obtain an insulin-like growth factor-1 (IGF-1) in patients with prolactinoma at the initial diagnosis. Long-term follow-up of IGF-1 is not routinely done. Here, we report two cases of well-controlled prolactinoma on dopamine agonists with the development of acromegaly 10-20 years after the initial diagnoses. In both patients, a mixed PRL/GH-cosecreting adenoma was confirmed on the pathology examination after transsphenoidal surgery (TSS). Therefore, periodic routine measurements of IGF-1 should be considered regardless of the duration and biochemical control of prolactinoma.

Learning Points: Acromegaly can develop in patients with well-controlled prolactinoma on dopamine agonists.The interval between prolactinoma and acromegaly diagnoses can be several decades.Periodic screening of patients with prolactinoma for growth hormone excess should be considered and can 
lead to an early diagnosis of acromegaly before the development of complications.
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http://dx.doi.org/10.1530/EDM-16-0069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093383PMC
October 2016

Geographic variation in cost of care for pituitary tumor surgery.

Pituitary 2016 Oct;19(5):515-21

Department of Neurosurgery, School of Medicine and Dentistry, University of Rochester Medical Center, 601 Elmwood Ave, Box 670, Rochester, NY, 14642, USA.

Purpose: Geography is known to affect cost of care in surgical procedures. Understanding the relationship between geography and hospital costs is pertinent in the effort to reduce healthcare costs. We studied the geographic variation in cost for transsphenoidal pituitary surgery in hospitals across New York State.

Methods: Using the Healthcare Cost and Utilization Project State Inpatient Database for New York from 2008 to 2011, we analyzed records of patients who underwent elective transsphenoidal pituitary tumor surgery and were discharged to home or self-care. N.Y. State was divided into five geographic regions: Buffalo, Rochester, Syracuse, Albany, and Downstate. These five regions were compared according to median charge and cost per day.

Results: From 2008 to 2011, 1803 transsphenoidal pituitary tumor surgeries were performed in New York State. Mean patient age was 50.7 years (54 % were female). Adjusting prices for length of stay, there was substantial variation in prices. Median charges per day ranged from $8485 to $13,321 and median costs per day ranged from $2962 to $6837 between the highest and lowest regions from 2008 to 2011.

Conclusion: Within New York State, significant geographic variation exists in the cost for transsphenoidal pituitary surgery. The significance of and contributors to such variation is an important question for patients, providers, and policy makers. Transparency of hospital charges, costs, and average length of stay for procedures to the public provides useful information for informed decision-making, especially for a highly portable disease entity like pituitary tumors.
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http://dx.doi.org/10.1007/s11102-016-0738-xDOI Listing
October 2016

Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome.

Blood 2016 Feb 4;127(5):616-25. Epub 2015 Dec 4.

Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.

In vitro evidence suggests that the bone marrow microenvironment (BMME) is altered in myelodysplastic syndromes (MDSs). Here, we study the BMME in MDS in vivo using a transgenic murine model of MDS with hematopoietic expression of the translocation product NUP98-HOXD13 (NHD13). This model exhibits a prolonged period of cytopenias prior to transformation to leukemia and is therefore ideal to interrogate the role of the BMME in MDS. In this model, hematopoietic stem and progenitor cells (HSPCs) were decreased in NHD13 mice by flow cytometric analysis. The reduction in the total phenotypic HSPC pool in NHD13 mice was confirmed functionally with transplantation assays. Marrow microenvironmental cellular components of the NHD13 BMME were found to be abnormal, including increases in endothelial cells and in dysfunctional mesenchymal and osteoblastic populations, whereas megakaryocytes were decreased. Both CC chemokine ligand 3 and vascular endothelial growth factor, previously shown to be increased in human MDS, were increased in NHD13 mice. To assess whether the BMME contributes to disease progression in NHD13 mice, we performed transplantation of NHD13 marrow into NHD13 mice or their wild-type (WT) littermates. WT recipients as compared with NHD13 recipients of NHD13 marrow had a lower rate of the combined outcome of progression to leukemia and death. Moreover, hematopoietic function was superior in a WT BMME as compared with an NHD13 BMME. Our data therefore demonstrate a contributory role of the BMME to disease progression in MDS and support a therapeutic strategy whereby manipulation of the MDS microenvironment may improve hematopoietic function and overall survival.
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http://dx.doi.org/10.1182/blood-2015-06-653113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742549PMC
February 2016

The hematopoietic stem cell niche in homeostasis and disease.

Blood 2015 Nov 14;126(22):2443-51. Epub 2015 Oct 14.

Departments of Medicine and Pathology & Immunology, Washington University School of Medicine, St. Louis, MO.

The bone marrow microenvironment contains a heterogeneous population of stromal cells organized into niches that support hematopoietic stem cells (HSCs) and other lineage-committed hematopoietic progenitors. The stem cell niche generates signals that regulate HSC self-renewal, quiescence, and differentiation. Here, we review recent studies that highlight the heterogeneity of the stromal cells that comprise stem cell niches and the complexity of the signals that they generate. We highlight emerging data that stem cell niches in the bone marrow are not static but instead are responsive to environmental stimuli. Finally, we review recent data showing that hematopoietic niches are altered in certain hematopoietic malignancies, and we discuss how these alterations might contribute to disease pathogenesis.
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http://dx.doi.org/10.1182/blood-2015-07-533588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661168PMC
November 2015

Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia.

PLoS One 2015 15;10(7):e0132375. Epub 2015 Jul 15.

Department of Medicine, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America.

Cytogenetically normal acute myeloid leukemia (CN-AML) patients harboring RUNX1 mutations have a dismal prognosis with anthracycline/cytarabine-based chemotherapy. We aimed to develop an in vivo model of RUNX1-mutated, CN-AML in which the nature of residual disease in this molecular disease subset could be explored. We utilized a well-characterized patient-derived, RUNX1-mutated CN-AML line (CG-SH). Tail vein injection of CG-SH into NOD scid gamma mice led to leukemic engraftment in the bone marrow, spleen, and peripheral blood within 6 weeks. Treatment of leukemic mice with anthracycline/cytarabine-based chemotherapy resulted in clearance of disease from the spleen and peripheral blood, but persistence of disease in the bone marrow as assessed by flow cytometry and secondary transplantation. Whole exome sequencing of CG-SH revealed mutations in ASXL1, CEBPA, GATA2, and SETBP1, not previously reported. We conclude that CG-SH xenografts are a robust, reproducible in vivo model of CN-AML in which to explore mechanisms of chemotherapy resistance and novel therapeutic approaches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132375PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503761PMC
May 2016

Biology of BM failure syndromes: role of microenvironment and niches.

Hematology Am Soc Hematol Educ Program 2014 Dec 18;2014(1):71-6. Epub 2014 Nov 18.

Division of Endocrinology, Department of Medicine, Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY.

The BM microenvironment and its components regulate hematopoietic stem and progenitor cell (HSC) fate. An abnormality in the BM microenvironment and specific dysfunction of the HSC niche could play a critical role in initiation, disease progression, and response to therapy of BM failure syndromes. Therefore, the identification of changes in the HSC niche in BM failure syndromes should lead to further knowledge of the signals that disrupt the normal microenvironment. In turn, niche disruption may contribute to disease morbidity, resulting in pancytopenia and clonal evolution, and its understanding could suggest new therapeutic targets for these conditions. In this chapter, we briefly review the evidence for the importance of the BM microenvironment as a regulator of normal hematopoiesis, summarize current knowledge regarding the role of dysfunctions in the BM microenvironment in BM failure syndromes, and propose a strategy through which niche stimulation can complement current treatment for myelodysplastic syndrome.
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http://dx.doi.org/10.1182/asheducation-2014.1.71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419374PMC
December 2014

Notch signaling in the malignant bone marrow microenvironment: implications for a niche-based model of oncogenesis.

Ann N Y Acad Sci 2015 Jan 28;1335:63-77. Epub 2014 Oct 28.

Hematopathology Unit, Department of Pathology, University of Rochester School of Medicine and Dentistry, Rochester, New York.

Fueled by the growing interest in stem cell biology and the promise of regenerative medicine, study of the hematopoietic stem cell (HSC) microenvironment has provided critical insights into normal and malignant hematopoiesis. Notch receptor signaling in this microenvironment is a critical regulator of HSC fate and differentiation. Notch signaling also has the potential to modulate the growth of various malignant cell types, as evidenced by the growing list of hematologic cancers and other malignancies associated with either mutations in Notch genes or alterations in Notch signaling. In both health and disease, activation of Notch signaling predominantly exerts influence through stromal cell interactions with the tumor or stem cell microenvironments. Definitive evidence from transgenic mouse models has shown that alterations in stromal cell signaling from the bone marrow niche can induce malignant outgrowth of preleukemic clones and leukemia. Understanding how Notch receptor signals in the bone marrow microenvironment govern stem cell behavior will advance our understanding of cancer pathogenesis in hematologic malignancies and may have implications for treating metastatic solid tumors involving bone. These microenvironmental interactions are potential therapeutic targets for treating and preventing a variety of diseases, including bone marrow failure disorders, myelodysplastic syndromes, leukemia, and lymphoma.
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http://dx.doi.org/10.1111/nyas.12562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289406PMC
January 2015

Osteoblasts as leukemia-initiating cells.

Bonekey Rep 2014 3;3:572. Epub 2014 Sep 3.

Department of Medicine, University of Rochester School of Medicine and Dentistry , Rochester NY, USA ; Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry , Rochester NY, USA ; Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry , Rochester NY, USA ; Endocrine Division, University of Rochester School of Medicine and Dentistry , Rochester NY, USA.

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http://dx.doi.org/10.1038/bonekey.2014.67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162463PMC
September 2014

Minireview: complexity of hematopoietic stem cell regulation in the bone marrow microenvironment.

Mol Endocrinol 2014 Oct 1;28(10):1592-601. Epub 2014 Aug 1.

Endocrine Division (C.M.H., L.M.C.), Department of Medicine, and Department of Pharmacology and Physiology (C.M.H.), University of Rochester School of Medicine, Rochester, New York 14642.

Hematopoiesis in vertebrates is sustained over the duration of an organism's lifetime due to strict regulation of the highly hierarchical hematopoietic system, where a few immature hematopoietic stem cells (HSCs) continuously regenerate the entire blood supply, which is constantly being replaced. Although HSCs self-regulate through cell-autonomous processes, they also receive a variety of signals from their microenvironment or niche. Within the microenvironment, HSCs are regulated through both cell-cell interactions and secreted signals, including hormones. HSCs at the apex of the blood supply integrate these signals to produce progeny to support hematopoiesis while simultaneously maintaining a stem cell pool. In the past 10 years, advances in genetic models and flow cytometry have provided the tools to test how the microenvironment regulates HSCs. This review is organized in 3 main parts and will focus on cellular components of the HSC niche that are potential targets for hormonal signals, then review critical regulatory signals in the HSC niche, and finally highlight the emerging role of hormonal and paracrine signals in the bone marrow.
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http://dx.doi.org/10.1210/me.2014-1079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179636PMC
October 2014

Impact of dietary supplements, obesity and treatment initiation on serum vitamin D levels in patients with lymphoma.

Leuk Lymphoma 2015 Feb 15;56(2):508-11. Epub 2014 Jul 15.

Division of Endocrinology, Department of Medicine.

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http://dx.doi.org/10.3109/10428194.2014.919633DOI Listing
February 2015

Hematopoietic stem cell cultures and assays.

Methods Mol Biol 2014 ;1130:315-324

University of Rochester Medical Center, Rochester, NY, USA.

The adult hematopoietic system is repopulated in its entirety from a rare cell type known as hematopoietic stem cells (HSCs) that reside in the marrow space throughout the skeletal system. Here we describe the isolation and identification of HSCs both phenotypically and functionally.
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http://dx.doi.org/10.1007/978-1-62703-989-5_24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419375PMC
September 2014

Osteolineage cells and regulation of the hematopoietic stem cell.

Authors:
Laura M Calvi

Best Pract Res Clin Haematol 2013 Sep 16;26(3):249-52. Epub 2013 Oct 16.

University of Rochester School of Medicine, 601 Elmwood Avenue, Box 693, Rochester, NY 14642, USA. Electronic address:

Over the last 10 years, progress has been made in understanding the relationship between hematopoietic stem cells and their microenvironment, or niche. Increased knowledge of the microenvironment and its effects on hematopoiesis and leukemogenesis based on murine models may lead to the identification of relevant new therapeutic targets for leukemia. In particular, the chemokine CCL3 has potential as a mediator of leukemia-induced microenvironmental changes, as it has been found to be increased in human acute myeloid leukemia.
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http://dx.doi.org/10.1016/j.beha.2013.10.004DOI Listing
September 2013

Cellular complexity of the bone marrow hematopoietic stem cell niche.

Calcif Tissue Int 2014 Jan 8;94(1):112-24. Epub 2013 Oct 8.

Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA,

The skeleton serves as the principal site for hematopoiesis in adult terrestrial vertebrates. The function of the hematopoietic system is to maintain homeostatic levels of all circulating blood cells, including myeloid cells, lymphoid cells, red blood cells, and platelets. This action requires the daily production of more than 500 billion blood cells. The vast majority of these cells are synthesized in the bone marrow, where they arise from a limited number of hematopoietic stem cells (HSCs) that are multipotent and capable of extensive self-renewal. These attributes of HSCs are best demonstrated by marrow transplantation, where even a single HSC can repopulate the entire hematopoietic system. HSCs are therefore adult stem cells capable of multilineage repopulation, poised between cell fate choices which include quiescence, self-renewal, differentiation, and apoptosis. While HSC fate choices are in part determined by multiple stochastic fluctuations of cell autonomous processes, according to the niche hypothesis, signals from the microenvironment are also likely to determine stem cell fate. While it had long been postulated that signals within the bone marrow could provide regulation of hematopoietic cells, it is only in the past decade that advances in flow cytometry and genetic models have allowed for a deeper understanding of the microenvironmental regulation of HSCs. In this review, we will highlight the cellular regulatory components of the HSC niche.
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http://dx.doi.org/10.1007/s00223-013-9805-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936515PMC
January 2014

Ovariectomy expands murine short-term hemopoietic stem cell function through T cell expressed CD40L and Wnt10B.

Blood 2013 Oct 16;122(14):2346-57. Epub 2013 Aug 16.

Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA;

Estrogen deficiency expands hemopoietic stem and progenitor cells (HSPCs) and mature blood lineages, but the involved mechanism and the affected HSPC populations are mostly unknown. Here we show that ovariectomy (ovx) expands short-term HSPCs (ST-HSPCs) and improves blood cell engraftment and host survival after bone marrow (BM) transplantation through a dual role of the T-cell costimulatory molecule CD40 ligand (CD40L). This surface receptor is required for ovx to stimulate T-cell production of Wnt10b, a Wnt ligand that activates Wnt signaling in HSPCs and stromal cells (SCs). Moreover, CD40L is required for ovx to increase SC production of the hemopoietic cytokines interleukin (IL)-6, IL-7, and granulocyte macrophage-colony-stimulating factor. Attesting to the relevance of CD40L and Wnt10b, ovx fails to expand ST-HSPCs in CD40L-null mice and in animals lacking global or T-cell expression of Wnt10b. In summary, T cells expressed CD40L, and the resulting increased production of Wnt10b and hemopoietic cytokines by T cells and SCs, respectively, plays a pivotal role in the mechanism by which ovx regulates hemopoiesis. The data suggest that antiestrogens may represent pharmacological targets to improve ST-HSPC function through activation of the microenvironment.
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http://dx.doi.org/10.1182/blood-2013-03-487801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3790505PMC
October 2013

Pituitary adenoma with mucin cells in a man with an unusual presentation of Carney complex.

Endocr Pathol 2013 Jun;24(2):106-9

Departments of Pathology and Laboratory Medicine and Ophthalmology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.

We describe a 44-year-old man with infertility, acromegaly, and hypergonadotropic hypogonadism. Clinical examination of the patient revealed hyperpigmented macules on the lips, buccal mucosa, and face which were histologically confirmed as cutaneous myxomas and blue nevi. Ultrasound revealed testicular calcifications and multiple hypoechoic thyroid nodules. MR imaging showed a pituitary microadenoma and resection revealed it to be a growth hormone and prolactin-secreting adenoma with the unusual finding of admixed individual mucin-producing cells. We discuss mucin cells in pituitary adenoma, an unreported pathologic finding in a patient with Carney complex.
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http://dx.doi.org/10.1007/s12022-013-9247-xDOI Listing
June 2013

Concise review: Current concepts in bone marrow microenvironmental regulation of hematopoietic stem and progenitor cells.

Stem Cells 2013 Jun;31(6):1044-50

Department of Pathology and Laboratory MedicineUniversity of Rochester School of Medicine, Rochester, New York 14642, USA.

Hematopoietic stem cell (HSC) behavior is governed in large part by interactions of the blood system with the bone microenvironment. Increasing evidence demonstrates the profound role the local HSC microenvironment or niche plays in normal stem cell function, in therapeutic activation and in the setting of malignancy. A number of cellular and molecular components of the microenvironment have been identified thus far, several of which are likely to provide exciting therapeutic targets in the near future. Clinically effective strategies for niche manipulation, however, require careful study of the interaction of these niche components. Some of the key findings defining these regulatory interactions are explored in this concise review, with special emphasis on potential translational applications.
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http://dx.doi.org/10.1002/stem.1370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664122PMC
June 2013

Two cases of malignant struma ovarii with metastasis to pelvic bone.

Gynecol Obstet Invest 2013 6;75(2):139-44. Epub 2013 Feb 6.

Division of Endocrinology and Metabolism, University of Rochester School of Medicine, Rochester, NY 14642, USA.

Histologically, malignant struma ovarii metastasizes rarely, and only a few cases reported bone metastasis. Here, we describe 2 cases of biologically malignant struma ovarii with pelvic bone metastasis. Case 1 is a 22-year-old female who was found to have a large left ovarian mass during routine prenatal ultrasound. Papillary thyroid cancer arising in struma ovarii was identified after laparoscopic salpingo-oophorectomy. After total thyroidectomy, radioactive iodine whole-body scan revealed extrathyroidal iodine uptake in left anterior pelvis. Subsequent I-131 treatment resolved the pelvic metastasis. Case 2 is a 49-year-old female who was diagnosed with malignant struma ovarii in 1996 and presented in 2007 with pelvic recurrence and extensive left hip metastasis. Treatment with resection of the pelvic tumor, total thyroidectomy, and multiple I-131 ablation led to eventual resolution of the abdominal and left hip foci. In conclusion, we present 2 rare cases of malignant struma ovarii, both with metastasis to the pelvic bone. This report makes pelvic bone the most frequent site for bone metastasis in malignant struma ovarii. It also emphasizes the importance of total thyroidectomy in allowing identification and treatment of bony metastasis with radioactive iodine.
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http://dx.doi.org/10.1159/000345863DOI Listing
August 2013