The Bone Marrow Niche, Stem Cells, and Leukemia: Impact of Drugs, Chemicals, and the Environment

The Bone Marrow Niche, Stem Cells, and Leukemia: Impact of Drugs, Chemicals, and the Environment

Wednesday, May 29, 2013 - Friday, May 31, 2013

The New York Academy of Sciences

Presented By

Presented by Rutgers, The State University of New Jersey and the New York Academy of Sciences

 

Over 20,000 Americans are diagnosed each year with bone marrow failure syndromes. Environmental, chemical, and genetic factors have been linked to the development of lymphomas, leukemias, and myelodysplastic syndromes (MDS). Additionally, some anti-cancer drugs have been shown to themselves induce DNA damage and secondary cancers. In light of increasing societal exposure to toxic environmental agents that may be carcinogenic, including chemicals and pharmaceuticals, we face the potential for a rise in the incidence of bone marrow failure and malignancy. In order to better understand leukemia it may be necessary to examine it from the perspective that it is an environmental disease.

To date, two separate groups of scientists and physicians have been studying bone marrow: toxicologists who examine the effects of chemicals and the environment on healthy marrow, and hematologists and oncologists who investigate bone marrow abnormalities and malignancies. Thus, there is a clear, unmet need for collaboration between these fields within academia, industry, and government in order to accelerate our investigation and understanding both of basic bone marrow biology and chemically-induced diseases of the marrow.

This 2.5-day conference will bring together representatives from two areas of research, toxicology and hematology, around a jointly shared goal — to better understand, prevent, and treat myeloid neoplasms. Conference Sessions will combine basic science and toxicology research at the level of the bone marrow niche with clinical findings from healthy subjects and patients. Topics for discussion will include bone marrow niche structure and function, the maturation and differentiation of healthy and leukemogenic hematopoietic stem cells, and the environmental, chemical, and genetic factors involved in the development of myeloid abnormalities including MDS and acute myeloid leukemia (AML). The meeting will feature a series of plenary lectures, panel discussions, a poster session, and short talk presentations selected from abstracts submitted by early career investigators.

Organizing Committee*

Conference Organizers

Michael A. Gallo, PhD

Robert Wood Johnson Medical School and Environmental and Occupational Health Sciences Institute; Rutgers, The State University of New Jersey

Helmut Greim, MD

Technical University of Munich

Robert Snyder, PhD (Chair)

Environmental and Occupational Health Sciences Institute; Rutgers, The State University of New Jersey

Subcommittee Chairs

Finance:

Robert Snyder, PhD

Environmental and Occupational Health Sciences Institute; Rutgers, The State University of New Jersey

International Advisory Committee:

Helmut Greim, MD

Technical University of Munich

Logistics:

Debra Kaden, PhD

Environ International Corporation

Programs:

Richard Larson, MD

University of Chicago

David Ross, PhD

University of Colorado Anschutz Medical Campus

Publications:

Jerry M. Rice, PhD

Georgetown University Medical Center

* Please click on the Speakers tab for a complete listing of the Organizing Committee

Registration Pricing

 By 4/26/2013After 4/26/2013Onsite
Member$350$400$500
Student/Postdoc Member$200$250$300
Nonmember (Academia)$400$450$550
Nonmember (Corporate)$500$550$650
Nonmember (Non-profit)$400$450$550
Nonmember (Student / Postdoc / Fellow)$200$250$300

 

Registration includes a complimentary, one-year membership to the New York Academy of Sciences. Complimentary memberships are provided to non-members only and cannot be used to renew or extend existing or expiring memberships. A welcome email will be sent upon registration which will include your membership credentials.

Presented by

  • The New York Academy of Sciences
  • Rutgers University

Agenda

* Presentation times are subject to change.


Day 1 — Wednesday, May 29, 2013

8:00 AM

Breakfast and Registration

8:45 AM

Opening Remarks
Melinda Miller, PhD, The New York Academy of Sciences
Helmut Greim, MD, Technical University of Munich
Christopher J. Molloy, PhD, RPh, Rutgers, The State University of New Jersey
Robert Snyder, PhD, Environmental and Occupational Health Sciences Institute; Rutgers, The State University of New Jersey

Session I. Stem Cells, the Niche and Myeloid Neoplasms

Session Chairs: Richard D. Irons, PhD, Fudan University; Dorothy A. Sipkins, MD, PhD, The University of Chicago

9:15 AM

Normal and Neoplastic Stem Cells
Irving Weissman, MD, Stanford University

9:45 AM

Myeloproliferative Neoplasm Development Remodels the Osteoblastic Bone Marrow Niche and Promotes Myelofibrosis
Emmanuelle Passegué, PhD, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco

10:15 AM

Niche Targeting of Leukemia Stem Cells
Catriona Jamieson, MD, PhD, University of California, San Diego

10:45 AM

Networking Break

11:15 AM

Niche and Signaling Regulation of the State and Fate of Stem Cells
Linheng Li, PhD, Stowers Institute for Medical Research

11:45 AM

Niche Initiated Oncogenesis
David T. Scadden, MD, Massachusetts General Hospital; Harvard University

12:15 PM

Contribution of the Reprogrammed Vascular Niche to Stem Cell Self-Renewal and Organ Regeneration
Shahin Rafii, MD, Weill Cornell Medical College

12:45 PM

Discussion Panel

1:00 PM

Networking Lunch

Session II. Stem Cell Signaling and the Niche

Session Chairs: David Ross, PhD, University of Colorado Anschutz Medical Campus; Emmanuelle Passegué, PhD, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco

2:00 PM

Niche-Secreted Factors Regulate Stem Cell Behavior
Robert Oostendorp, PhD, Technical University of Munich

2:30 PM

The Ah Receptor in Stem Cell Cycling, Regulation and Quiescence
Thomas A. Gasiewicz, PhD, University of Rochester Medical Center

3:00 PM

Stress Induced Activation of Hematopoietic Stem Cells In Vivo
Marieke A. G. Essers, PhD, Heidelberg Institute for Stem Cell Technology and Experimental Medicine; German Cancer Research Center

3:30 PM

Networking Break

4:00 PM

Aldehyde Dehydrogenases in Normal and Malignant Hematopoietic Stem Cells
Clayton Smith, MD, University of Colorado, Denver

4:30 PM

Niche Regulation for Hematopoietic Stem Cells
Toshio Suda, MD, PhD, School of Medicine, Keio University

5:00 PM

Apoptosis-Related Gene Expression Profiling of Hematopoietic Stem/Progenitor Cells After Radiation Exposure
Yoko Hirabayashi, MD, National Institute of Health Sciences

5:30 PM

Discussion Panel

5:45 PM

Short Talks Selection

Endothelial Cells Expressing Constitutively Active AKT1 Combined With Mesenchymal Stem Cells Are Capable of Reconstituting Bone Marrow Niche In Vitro
Irina A. MeIn, MSc, Almazov Federal Heart, Blood and Endocrinology Centre

Reconstructing the Human Hematopoietic Niche: Opportunities for Studying Normal and Malignant Hematopoiesis
Richard W. J. Groen, PhD, Dana-Farber Cancer Institute

6:15 PM

Poster Session and Networking Reception

8:00 PM

Close of Day 1

Day 2 — Thursday, May 30, 2013

7:45 AM

Registration and Breakfast

8:00 AM

Early-Career Investigator Training: Writing for Scientific Publication
Douglas Braaten, PhD, Editor-in-Chief, Annals of the New York Academy of Sciences

Session III. Dysregulation of Gene Expression in Myeloid Neoplasms

Session Chairs: Michelle M. Le Beau, PhD, The University of Chicago Comprehensive Care Center; Martyn T. Smith, PhD, University of California, Berkeley

9:00 AM

Epigenetic Mechanisms and Therapeutics
Lucy A. Godley, MD, PhD, The University of Chicago

9:30 AM

Gene Expression in Myelodysplastic Syndromes and Acute Myeloid Leukemia
Stephen Nimer, MD, University of Miami

10:00 AM

Role of Mutations In Epigenetic Regulators in Pathogenesis of Myeloid Malignancies
Ross L. Levine, MD, Memorial Sloan Kettering Cancer Center

10:30 AM

MicroRNAs in Myeloid Leukemia
Guido Marcucci, MD, Wexner Medical Center at The Ohio State University

11:00 AM

Networking Break

11:30 AM

Application of Genome-Wide Profiling to Evaluate Effects of Benzene and its Metabolites from Yeast to Human
Luoping Zhang, PhD, School of Public Health, University of California, Berkeley

12:00 PM

Benzene Cytogenetics, Myelodysplasia and Acute Myeloid Leukemia: New Insights Into a Disease Continuum
Richard D. Irons, PhD, Fudan University

12:30 PM

Preventing Leukemogenic Chromosomal Translocations
Robert Hromas, MD, University of Florida Department of Medicine

1:00 PM

Discussion Panel

1:15 PM

Networking Lunch

Session IV. Therapy Related Myeloid Neoplasms

Session Chairs: David Eastmond, MS, PhD, University of California, Riverside; Richard Larson, MD, The University of Chicago

2:30 PM

Genetics of Therapy-Related Myelodysplastic Syndromes and Acute Myeloid Leukemia
Mette Klarskov Andersen, MD, PhD, Rigshospitalet, Denmark

3:00 PM

Genetic Pathways Leading to Alkylating Agent-Induced Therapy-Related Myeloid Neoplasms
Michelle M. Le Beau, PhD, The University of Chicago Comprehensive Care Center

3:30 PM

Topoisomerase II and Leukemia
Neil Osheroff, PhD, Vanderbilt University School of Medicine

4:00 PM

Networking Break

4:30 PM

Familial Myelodysplastic Syndromes/Acute Myeloid Leukemia and Germline RUNX1 Mutations
Jane E. Churpek, MD, University of Chicago Hospitals

5:00 PM

The Genetics of Therapy-Induced Second Cancer Risk
Kenan Onel, MD, PhD, The University of Chicago

5:30 PM

Discussion Panel

5:45 PM

Short Talks Selection

Investigation into the Cross Talk Between Acute Myeloid Leukemia Cells and the Bone Marrow Microenvironment
Ashley Hamilton, PhD, Cancer Research UK, London Research Institute

Functional Analysis of the Bone Marrow Microenvironment in Myelodysplastic Syndrome: Targeting the Disease Niche
Ruben A. Ferrer, MD, University Hospital Carl Gustav Carus at Dresden University of Technology

6:15 PM

Close of Day 2

Day 3 — Friday, May 31, 2013

8:30 AM

Breakfast

Session V. Models and Tools

Session Chairs: Lucy A. Godley, MD, PhD, The University of Chicago; Robert Oostendorp, PhD, Technical University of Munich

9:00 AM

Regulation of Leukemia Cell Dormancy by The Bone Marrow Niche
Dorothy A. Sipkins, MD, PhD, The University of Chicago

9:30 AM

Methods to Analyze Homing of Stem Cells in Bone Marrow
Susie K. Nilsson, PhD, Commonwealth Scientific and Industrial Research Organization (CSIRO)

10:00 AM

Modeling Exposure-Induced Leukemogenesis in the Mouse
Michael J. Thirman, MD, The University of Chicago

10:30 AM

Networking Break

11:00 AM

Redox Proteomics for Measurement of Oxidative Stress
Dean P. Jones, PhD, Emory University

11:30 AM

Long-term Quantitative Single Cell Imaging: New Tools for Old Questions
Timm Schroeder, PhD, Helmholtz Center Munich

12:00 PM

Genome-Exposome Interactions in Leukemia Etiology
Martyn T. Smith, PhD, University of California, Berkeley

12:30 PM

Discussion Panel

12:45 PM

Closing Remarks

1:00 PM

Close of Conference

Speakers

Speakers

Mette Klarskov Andersen, MD, PhD

Rigshospitalet, Denmark

Jane E. Churpek, MD

University of Chicago Hospitals

Marieke Essers, PhD

Heidelberg Institute for Stem Cell Technology and Experimental Medicine; German Cancer Research Center

Thomas A. Gasiewicz, PhD

University of Rochester Medical Center

Lucy A. Godley, MD, PhD

The University of Chicago

Yoko Hirabayashi, MD

National Institute of Health Sciences

Robert Hromas, MD

University of Florida Department of Medicine

Richard D. Irons, PhD

Fudan University

Dean P. Jones, PhD

Emory University

Michelle M. Le Beau, PhD

The University of Chicago Comprehensive Cancer Center

Linheng Li, PhD

Stowers Institute for Medical Research

Guido Marcucci , MD

Wexner Medical Center at The Ohio State University

Susie K. Nilsson, PhD

Commonwealth Scientific and Industrial Research Organisation (CSIRO)

Stephen Nimer, MD

University of Miami

Kenan Onel, MD, PhD

The University of Chicago

Robert A. J. Oostendorp, PhD

Technical University of Munich

Neil Osheroff, PhD

Vanderbilt University School of Medicine

Emmanuelle Passegué, PhD

The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at University of California, San Francisco

Shahin Rafii, MD

Weill Cornell Medical College

David T. Scadden, MD

Massachusetts General Hospital; Harvard University

Timm Schroeder, PhD

Helmholtz Center Munich

Dorothy A. Sipkins, MD, PhD

The University of Chicago

Martyn T, Smith, PhD

University of California, Berkeley

Clayton Smith, MD

University of Colorado, Denver

Toshio Suda, MD, PhD

School of Medicine, Keio University

Michael J. Thirman, MD

The University of Chicago

Irving Weissman, MD

Stanford University

Luoping Zhang, PhD

School of Public Health, University of California, Berkelely

Organizing Committee

Subcommittee Abbreviations:

FINFinance Subcommittee
IACInternational Advisory Committee
LOGLogistics Subcommittee
PROPrograms Subcommittee
PUBPublications Subcommittee

 * Denotes Subcommittee Chair/Co-Chair

 

Patrick Beatty, PhD [FIN]

American Petroleum Institute

Hermann Bolt, MD, PhD [IAC]

University of Dortmund

David Eastmond, MS, PhD [PRO]

University of California, Riverside

John E. French, PhD [PRO, PUB]

National Institute for Environmental Health Sciences, National Institutes of Health

Michael A. Gallo, PhD [FIN, PRO, PUB]

Robert Wood Johnson Medical School and Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey

Bernard D. Goldstein, MD

University of Pittsburgh

Helmut Greim, MD [FIN, IAC*]

Technical University of Munich

Rogene Henderson, PhD

Lovelace Respiratory Research Institute

Yoko Hirabayashi, MD [IAC]

National Center for Biological Safety and Research, National Institute of Health Sciences, Japan

Tohru Inoue, MD, PhD [IAC]

ToxSCO (ToxSafety Consultations) and Nihon University School of Medicine

Richard D. Irons, MT, PhD [IAC, PRO]

University of Colorado, Fudan University, and Cinpathogen Inc.

Debra Kaden, PhD [LOG*, PUB]

Environ International Corporation

Richard Larson, MD [IAC, PRO*, PUB]

University of Chicago

Serrine S. Lau, PhD

University of Arizona

Terrance J. Monks, PhD

University of Arizona

Eileen Murphy, PhD [FIN, LOG]

Rutgers, The State University of New Jersey

Franz Oesch, PhD [IAC]

University of Mainz

Robert A. J. Oostendorp, MD [IAC, PRO]

Technical University of Munich

Christine Palermo, PhD, DABT [FIN, LOG, PUB]

ExxonMobil Biomedical Sciences, Inc.

David Pyatt, PhD [LOG]

Summit Toxicology, LLP and University of Colorado

Jerry M. Rice, PhD [FIN, PUB*]

Georgetown University Medical Center

David Ross, PhD [PRO*, PUB]

University of Colorado Anschutz Medical Campus

A. Robert Schnatter, MS, MSc, DPh

ExxonMobil Biomedical Sciences, Inc.

Dieter Schrenk, MD, PhD [IAC]

University of Kaiserlauthern

Dorothy Sipkins, MD [PRO]

University of Chicago

Martyn T. Smith, PhD

University of California, Berkeley

Babasaheb R. Sonawane, PhD

U.S. Environmental Protection Agency

Robert Snyder, PhD [FIN*, IAC, LOG]

Environmental and Occupational Health Sciences Institute; Rutgers, The State University of New Jersey

Michael A. Trush, PhD [PRO]

Johns Hopkins Bloomberg School of Public Health

Helmut Zarbl, PhD

Cancer Institute of New Jersey; UMDNJ - Robert Wood Johnson Medical School; Environmental and Occupational Health Sciences Institute; Rutgers, The State University of New Jersey

Luoping Zhang, MS, PhD [PUB]

School of Public Health, University of California, Berkeley

Sponsors

Bronze Sponsors

American Chemistry Council's Center for Advancing Risk Assessment Science and Policy

American Petroleum Institute

CONCAWE

Academy Friends

European Research Group on Environment and Health in the Transport Sector (EUGT e.V.)

Leukemia & Lymphoma Society

Society of Toxicology

United States Environmental Protection Agency

Grant Support

This conference is supported by an educational grant from Millennium Pharmaceuticals, Inc., The Takeda Oncology Company.

Funding for this conference was made possible (in part) by 1R13 ES022912-01 from the National Institute of Environmental Health Sciences and National Cancer Institute. The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.

Promotional Partners

American Society for Blood and Marrow Transplantation

American Society for Pharmacology & Experimental Therapeutics (ASPET)

American Society of Hematology

Aplastic Anemia & MDS International Foundation

British Society of Toxicological Pathology

Cancer Stem Cell News

Cell Therapy News

Cord Blood News

Environmental Health Perspectives

European Hematology Association

Hematopoiesis News

The Journal of Clinical Investigation

Journal of Experimental Medicine

Keystone Symposia on Molecular & Cellular Biology

Nature

The New York Academy of Medicine


Presented by

  • The New York Academy of Sciences
  • Rutgers University

Abstracts — Day 1

Normal and Neoplastic Stem Cells
Irving Weissman, MD, Stanford University

Following embryonic development, most of our tissues and organs are continuously regenerated from tissue/organ specific stem cells. The principal property that distinguishes such stem cells from their daughter cells is self-renewal; when stem cells divide they give rise to stem cells (by self-renewal) and progenitors (by differentiation). In most tissues, only the primitive stem cells self-renew. Stem cell isolation and transplantation is the basis for regenerative medicine. Self-renewal is dangerous, and therefore strictly regulated. Poorly regulated self renewal can lead to the genesis of cancer stem cells, the only self-renewing cells in the cancerous tumor. The Weissman lab has followed the progression from hematopoietic stem cells to myelogenous leukemias. They have found that the developing cancer clones progress at the stage of hematopoietic stem cells, until they become fully malignant. At this point, the ‘leukemia’ stem cell moves to a stage of a downstream oligolineage or multilineage progenitor that has evaded programmed cell death and programmed cell removal, while acquiring or keeping self-renewal. While there are many ways to defeat programmed cell death and senescence, there appears to be one dominant method to avoid programmed cell removal — the expression of the cell surface ‘don’t eat me’ protein, CD47, the ligand for macrophage SIRP-alpha. All cancers tested express CD47 to overcome expression of ‘eat me’ signals such as calreticulin and asialogylycoproteins. Antibodies that block the CD47–SIRP-alpha interaction enable phagocytosis and killing of the tumor cells in vitro and in vivo.
 

Myeloproliferative Neoplasm Development Remodels the Osteoblastic Bone Marrow Niche and Promotes Myelofibrosis
Emmanuelle Passegué, PhD, The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, San Francisco

Hematopoietic stem cell (HSC) function is influenced by the activity of bone marrow (BM) niche cells, including mesenchymal stem cells (MSC) and their osteoblastic lineage cell (OBC) derivatives. We show that the development of myeloproliferative neoplasms (MPN), such as chronic myelogenous leukemia (CML), causes a severe remodeling of the BM microenvironment and negatively affects the ability of OBCs to support HSC function. This remodeling is a direct consequence of leukemic myeloid cells stimulating MSCs to overproduce functionally altered OBC derivatives, which accumulate in the BM cavity as inflammatory myelofibrotic cells. These remodeled OBCs, in turn, show profound molecular and functional deregulations, and favor myeloid differentiation at the expense of HSC maintenance. These changes preferentially affect the activity of normal HSCs with minimal effect on the leukemic stem cell (LSC) activity of transformed HSCs. Taken together, our results describe a novel self-reinforcing mechanism wherein MPN development remodels the osteoblastic BM niche and creates a leukemic niche that promote myelofibrosis and impaired maintenance of normal hematopoiesis. Targeting this vicious interplay could represent a novel avenue to treat myeloid malignancies and restore normal blood function.
 

Niche Targeting of Leukemia Stem Cells
Catriona Jamieson, MD, PhD, University of California, San Diego

Human leukemia stem cells (LSC) evolve from progenitors as a result of acquisition of subversion of stem cell properties, such as self-renewal, survival and dormancy. This process of malignant progenitor reprogramming occurs in inflammatory niches, in part, through alternative GSK3beta and BCL2 family gene splice isoform expression that promotes LSC maintenance. Lentivirally enforced expression of BCR-ABL and JAK2 promotes TNF and STAT-mediated activation of adenosine deaminase RNA associated (ADAR1), which contributes to RNA editing and alternative splicing. While shRNA knockdown of ADAR1 prevents LSC self-renewal in blast crisis CML humanized mouse models, overexpression leads to myeloid progenitor expansion and GSK3beta missplicing. Deregulation of GSK3beta prevents phosphorylation and degradation of both beta-catenin and GLI sonic hedgehog pathway transcriptional activators resulting in increased LSC self-renewal, survival and dormancy. Recent pre-clinical and clinical studies demonstrate that sonic hedgehog inhibition abrogates LSC dormancy and survival thereby reducing maintenance in the niche. Furthermore, whole transcriptome RNA sequencing reveals that these LSC upregulate pro-survival BCL2 isoforms and downregulate pro-apoptotic genes in the marrow niche, which can be abrogated by a novel panBCL2 inhibitor, sabutoclax. This panBCL2 inhibitor targets quiescent LSC in the marrow and prolongs survival of serially transplanted recipients while sparing normal hematopoietic stem cells thereby providing the impetus for scale up and production for potential LSC targeted clinical trials that will obviate relapse.
 

Niche and Signaling Regulation of the State and Fate of Stem Cells
Linheng Li, PhD, Stowers Institute for Medical Research

Hematopoietic stem cells (HSCs) are maintained in balance between quiescent state and proliferating state. While proliferating HSCs are critical for supporting the routine blood production, quiescent HSCs are essential for long-term maintenance and also can be roused to replenish lost active HSCs. How the different states of HSCs are regulated is a fundamental question. The underlying signaling to regulate the quiescence and activation in different niches remains largely unknown. To address this question, we have analyzed the expression profile of Wnt receptors, Frizzleds, in HSCs. We found that noncanonical Wnt signaling — via receptor Frizzled8 (Fz8) and co-receptor Flamingo — presents in and functionally maintains quiescent HSCs in the endosteal (an inner bone surface) zone. Recently, we detected another noncanonical Wnt receptor, Frizzled5 (Fz5), is expressed in metabolically active (indicated by Mitotracker) HSCs and also in Nestin-GFP+ mesenchymal stem cells (MSCs) in the perivascular zone of central marrow. Fz5 is not expressed in H2B-GFP label-retaining quiescent HSCs, or in endosteal cells, or in sinusoidal cells. Using an Mx1-Cre:Fz5 knockout mouse model, we found a 60% decrease of HSCs isolated from central marrow, but no change in HSCs isolated from endosteum. Functionally, hematopoietic reconstitution was not affected in the primary transplantation, but was substantially decreased (by 80%) in the secondary transplantation compared to the control. This indicates that Fz5 maintains HSCs in the perivascular zone. We propose that noncanonical Wnt signaling maintains quiescent and active HSCs residing, respectively, in the endosteal and perivascular zones. In these zones, Fz8 and Fz5 are differentially expressed and mediate noncanonical Wnt signaling to maintain HSCs in the endosteal niche and to regulate active HSCs in the perivascular niche.
 

Niche Initiated Oncogenesis
David T. Scadden, MD, Massachusetts General Hospital; Harvard University

The microenvironment in which tumor cells reside is a recognized modulator of tumor cell behavior. Whether that environment can participate in the induction of cancer is less clear and difficult to investigate, in part, because of our limited understanding of the specific cell types comprising ‘stroma.’ The hematopoietic system has been informative in exploring multiple aspects of tissue homeostasis and malignant transformation. Among these, is defining heterologous cells in the microenvironment that can serve a regulatory role including the regulation of hematopoietic stem cells. Specific mesenchymal cells in bone have been shown to serve as niche components for stem cells in the bone marrow stroma. By genetically modifying subsets of osteolineage cells, we induced perturbation of stem cell function and caused disordered hematopoiesis. The resulting myelodysplasia was microenvironment dependent and resulted in the emergence of a frank leukemia with distinctive secondary genetic abnormalities.These genetic abnormalities did not include the gene deletion we induced in the microenvironement. The multi-step process of oncogenesis may then include an initiating step in heterologous cells that comprise ‘stroma.’ To test whether a dependence on stroma was retained, we transplanted the leukemic cells and found that the leukemia could only engraft in recipients who had the genetically altered osteolineage cells. Therefore the interaction between the microenvironmental cells and the hematopoietic cells was capable of initiating malignancy and appeared to be necessary for its maintenance. The dependence on interaction between cell types offers the potential for intervention at the points of cell-cell interaction in treatment and prevention strategies.
 

Contribution of the Reprogrammed Vascular Niche to Stem Cell Self-Renewal and Organ Regeneration
Jason M. Butler, PhD, Bisen Ding, PhD, Daylon James, PhD, Daniel Nolan, PhD, Michael Ginsberg, PhD, Sina Rabbany, PhD, and Shahin Rafii, MD, Weill Cornell Medical College, Ansary Stem Cell Institute; Howard Hughes Medical Institute, New York

Organ specific endothelial cells (ECs) are not just passive conduits to deliver oxygen and nutrients, but also establish an instructive vascular niche, which by elaboration of specific paracrine trophogens, (known as angiocrine factors), directly balance the rate of stem cell self-renewal and differentiation. Activation of Akt-mTOR pathway in the sinusoidal ECs (SECs) stimulates expression of angiocrine factors, including Notch-ligands, Wnts, FGFs and TGF modulators, that induce expansion of authentic hematopoietic stem cells (Cell Stem Cell, 3:251-64. 2010). While MAPkinase induces expression of angiocrine factors, that support differentiation of the stem cells into lineage committed progenitors.
 
After partial hepatectomy, SECs within the liver stimulated regeneration by angiocrine expression of Wnt2 and HGF (Nature, 468(7321):310-5, 2010). Pulmonary capillary ECs (PCECs), by deploying MMP14 and release of EGF ligands, sustain lung regeneration. Notably, transplantation of SECs or PCECs into mice restores organ regeneration (Cell, 47(3):539-53, 2011). These data establish the remarkable tissuespecific vascular heterogeneity in orchestrating organ regeneration.
 
To translate these findings to the clinical setting, we have differentiated human and mouse embryonic stem and iPSC cells into induced vascular endothelial cells (iVECs) (Cell, 151, 559-75, 2012). However, iVECs are unstable and have limited expansion potential. To circumvent this hurdle, we have developed new strategies by transcriptional reprogramming of amniotic cells into vascular ECs (rAC-VECs) (Cell, 151, 559-75, 2012). rACVECs phenocopy the specialized tissue-specific function of ECs, supporting long-term expansion of repopulating cells (Developmental Cell, In Press), such as hematopoietic stem cells in xenobiotic-free conditions. Given that rACVECs can be HLA-typed, cryopreserved, and publicly banked, these cells could establish an inventory for generating abundant tissue-specific vascular niche cells for promoting angiocrine-dependent organ regeneration.
 

Niche-Secreted Factors Regulate Stem Cell Behavior
Robert Oostendorp, PhD, Technical University of Munich

Somatic stem cells are critical to maintain highly regenerative tissues such as the skin, the gastro-intestinal mucosa and the blood system. Although it has long been known that hematopoietic stem cells (HSC) are located in the bone marrow, the surrounding micro-environment — the so-called niche — is thought to control the balance between HSC self-renewal and differentiation and may control HSC dormancy and proliferation. The molecular mechanisms involved in this regulation are, however, largely unknown. Most investigators, including our group, have started dissecting these mechanisms using in vitro models of the niche: stromal cell lines. The knowledge gathered in this manner is now validated in vivo. Our data shows that factors secreted by the niche, such as Sfrp1 and Ptn play a critical role in maintaining HSC self-renewal and the balance between myeloid and lymphoid regenerative potential. One of the main HSC pathways affected is the Wnt signaling pathway, as well as associated Smad-signaling modulators. In particular, the niche seems to have a critical role in maintaining the balance between canonical and non-canonical Wnt signaling in HSC. Disturbances in secretion of niche factors may thus dysregulate HSC pathways, facilitating disturbances in self-renewal and differentiation. In ultimate cases, this may lead to malignant transformation. Thus, the knowledge generated will aid in developing new tools for early detection of malignant transformation, as well as help improve therapies for eradicating malignant disease.
 

The Ah Receptor in Stem Cell Cycling, Regulation and Quiescence
Thomas A. Gasiewicz, PhD, University of Rochester Medical Center

Processes that regulate quiescence, self-renewal, and senescence of hematopoietic stem cells (HSCs) are not well understood. Due in part to the ability of xenobiotic ligands to have persistent effects on the immune system in experimental animals, there has been much work to define a physiological role of the aryl hydrocarbon receptor (AhR) and relationships to human disease. Persistent AhR activation by dioxin, a potent agonist, results in altered numbers and function of HSCs in mice. HSCs from AhR null-allele (KO) mice are hyperproliferative and have altered cell cycle. In addition, aging KO mice show characteristics consistent with premature bone marrow senescence and are prone to hematopoietic disease development. Furthermore, the Ahr gene appears to be regulated under conditions that control HSC proliferation. These data, and others, present a compelling argument for a function of the AhR in HSC regulation. We propose that the increased proliferation of HSCs lacking AhR expression or activity is a result of loss of quiescence, and as such, AhR normally acts as a negative regulator to curb excessive or unnecessary proliferation. Similarly, prolonged and/or inappropriate stimulation of AhR activity may compromise the ability of HSCs to sense environmental signals that allow these cells to balance quiescence, proliferation, migration, and differentiation. These data also support a hypothesis that deregulation of AhR function has an important role in the etiology and/or progression of certain hematopoietic diseases, many of which are associated with aging.
 
Supported by NIH Grants ES01247, ES07026, and ES04862.

Stress Induced Activation of Hematopoietic Stem Cells In Vivo
Stefanie Thamm, Raphael Lutz, Andrea Kuck, Stephan Wurzer, Marieke A.G. Essers, PhD, HI-STEM and DKFZ

Tissue stem cells are responsible for the maintenance and repair of most organs and tissues. In the hierarchical organized blood system, dormant hematopoietic stem cells (HSCs) with lifelong self-renewal capacity are at the top of the hierarchy, giving rise to active HSCs that typically control the blood cell production during healthy homeostasis. However, under stress conditions such as during virus infections or after blood loss, where large amounts of mature blood cells are lost, feedback signals are thought to signal back to the dormant HSCs, leading to their activation, and thus production of new mature blood cells. The molecular and cellular mechanisms, including which cytokines are part of these feedback loops, remain largely unexplored.
 
Our work has recently demonstrated that, very surprisingly, the cytokine IFNα, which is produced by virally infected immune cells to block the infection of more mature blood cells, is able to activate the entire HSC pool including dormant HSCs. Activated HSCs start to proliferate in vivo and up-regulate stem cell antigen 1 (Sca-1). In order to explain this surprising effect of IFNα on HSCs, we are currently exploring whether during infections IFNα might be part of a feedback loop leading to the activation of HSCs. Using a reporter mouse to monitor IFNα production in the bone marrow, several forms of bone marrow stress were tested. Interestingly, injection of mice with lipopolysaccharide (LPS) lead to increased IFNα production, followed by a TLR4-dependent activation of quiescent HSCs. Similar to IFNα, LPS induced activation is accompanied by and dependent on up-regulation of Sca-1 on the surface of HSCs. However, though IFNα has a direct effect on HSCs, both in vivo and in vitro experiments show that LPS has an indirect effect on HSCs. We are currently unraveling the mechanism underlying the indirect activation of HSCs in response to LPS and the potential role the bone marrow niche plays in this process. These data will further increase our knowledge on the mechanism of activation of HSCs under stress conditions.
 

Aldehyde Dehydrogenases in Normal and Malignant Hematopoietic Stem Cells
Clayton Smith, MD, University of Colorado, Denver

Hematopoietic stem cells (HSCs) sustain hematopoiesis in a highly controlled fashion through a dynamic balance of self-renewal, differentiation, apoptosis and other processes. Perturbation of these processes can lead to marrow failure, myelodysplasia (MDS), chronic or acute leukemia and other diseases. Control of these processes occurs through a complex interplay between HSCs and their microenvironment, as well as through increasingly well-characterized cellular processes. We have found that the Aldehyde Dehydrogenase (ALDH) gene family, which consists of at least 19 members, may also play an important role in regulating HSC cell fate decisions by metabolizing reactive oxygen species (ROS) and reactive aldehydes (RAld). Data from our group and others suggest that the intracellular ROS and RAld can provide fine level control over a variety of normal cellular process, as well as cause protein and DNA damage leading to cellular dysfunction. As an example, we have found that loss of 2 ALDH family isoforms in HSCs, ALDH1A1 and ALDH3A1, leads to increases in intracellular ROS and reactive aldehydes and widespread perturbations in cell signaling, gene expression and cell cycle progression, as well as a predisposition to leukemia formation. Approximately 1/3 of human leukemias also fail to express ALDH1A1 and ALDH3A1 and are exquisitely sensitive to toxic ALDH substrates. These observations set the stage for future studies designed to understand better the role of ROS and RAld in normal and malignant stem cells and to develop new therapies for AML, MDS and other disorders.
 

Niche Regulation for Hematopoietic Stem Cells
Toshio Suda, MD, PhD, School of Medicine, Keio University

Hematopoietic stem cells (HSCs) are sustained in a specific microenvironment known as the stem cell niche. Adult HSCs are kept quiescent during the cell cycle in the endosteal niche of the bone marrow (BM). The quiescent state is thought to be a characteristic property for the maintenance of HSCs. Normal HSCs maintain intracellular hypoxia, stabilize the hypoxia-inducible factor-1α (HIF-1α) protein and generate ATP by anaerobic metabolism. In HIF-1α-deficiency, HSCs become metabolically aerobic, lost cell cycle quiescence, and finally exhausted. An increased dose of HIF-1α protein in VHL mutated HSCs and their progenitors induced cell cycle quiescence and accumulation of HSCs in the BM. Restored glycolysis by pyruvate dehydrogenase kinases ameliorated cell cycle quiescence and stem cell capacity. Taken together, HSCs directly utilize the hypoxic microenvironment to maintain their cell cycle by HIF-1α-dependent metabolism. On the basis of the physiological nature of HSCs, I would like to discuss the abnormal HSCs and niches in hematological malignancies; multiple myeloma and chronic myelogenous leukemia (CML). Comparison between normal and abnormal HSCs and niches will be important to development of the new treatment for the cancer.
 

Apoptosis-Related Gene Expression Profiling of Hematopoietic Stem/Progenitor Cells after Radiation Exposure
Yoko Hirabayashi, MD, National Institute of Health Sciences

Because senescence is considered to be related to xenobiotic responses to ‘time’, a series of quantitative and qualitative studies was conducted, specifically focusing on the evaluation of hematopoietic stem/progenitor cells with or without radiation exposure followed by natural aging. As a result, the lineage negative, c-kit positive, stem cell antigen positive (LKS) fraction did not recover in 2Gy whole-body irradiated mice but remained at approximately 50-80% of those in age-matched nonirradiated controls until 18 months of age. Accordingly, the expression of genes, specifically those related to apoptosis, was elucidated by microarray data from mice one month after whole-body irradiation, and was quantitatively evaluated by real-time PCR analysis using bone-marrow cells and cells in the LKS fraction from 21-month-old mice with or without radiation exposure at 6 weeks of age, in comparison with 2-month-old non-irradiated control mice. In mice more than one year after radiation exposure, five out of eleven selected genes showed significant alterations of expression patterns. Among them, Ccnd1, Fyn, and Pik3r1 showed up-regulation of their expressions in the LKS fraction with radiation exposure compared with the fraction without radiation exposure. These findings may indicate a possible prolonged proliferation of cells in the LKS fraction after single-dose irradiation. Interestingly, the increased expression level of Ccnd1 was observed, specifically in mice with radiation exposure, in addition to the up-regulation of the gene in the LKS fraction of aged mice. These findings suggest that the aging phenotype may be enhanced by radiation exposure.
 

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