Publications by authors named "Marc H G P Raaijmakers"

28 Publications

  • Page 1 of 1

RUNX1 germline variants in RUNX1-mutant AML: how frequent?

Blood 2021 Mar;137(10):1428-1431

Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1182/blood.2020008478DOI Listing
March 2021

Aging of the Hematopoietic Stem Cell Niche: An Unnerving Matter.

Cell Stem Cell 2019 09;25(3):301-303

Erasmus Medical Center Cancer Institute, Department of Hematology, Faculty Building Rm Ee-1393. dr. Molewaterplein 50, 3015GE Rotterdam, the Netherlands. Electronic address:

The drivers of aging in the hematopoietic system remain incompletely understood. In this issue of Cell Stem Cell, Ho et al. (2019) report that functional switching of β-adrenergic nerve signaling underlies remodeling of stem cell niches, driving age-associated alterations in hematopoiesis.
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http://dx.doi.org/10.1016/j.stem.2019.08.008DOI Listing
September 2019

Early growth response 1 regulates hematopoietic support and proliferation in human primary bone marrow stromal cells.

Haematologica 2020 05 1;105(5):1206-1215. Epub 2019 Aug 1.

Division of Molecular Hematology, Department of Laboratory Medicine, Lund University, Lund, Sweden

Human bone marrow stromal cells (BMSC) are key elements of the hematopoietic environment and they play a central role in bone and bone marrow physiology. However, how key stromal cell functions are regulated is largely unknown. We analyzed the role of the immediate early response transcription factor EGR1 as key stromal cell regulator and found that EGR1 was highly expressed in prospectively-isolated primary BMSC, down-regulated upon culture, and low in non-colony-forming CD45 stromal cells. Furthermore, EGR1 expression was lower in proliferative regenerating adult and fetal primary cells compared to adult steady-state BMSC. Overexpression of EGR1 in stromal cells induced potent hematopoietic stroma support as indicated by an increased production of transplantable CD34CD90 hematopoietic stem cells in expansion co-cultures. The improvement in bone marrow stroma support function was mediated by increased expression of hematopoietic supporting genes, such as and Furthermore, EGR1 overexpression markedly decreased stromal cell proliferation whereas EGR1 knockdown caused the opposite effects. These findings thus show that EGR1 is a key stromal transcription factor with a dual role in regulating proliferation and hematopoietic stroma support function that is controlling a genetic program to co-ordinate the specific functions of BMSC in their different biological contexts.
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http://dx.doi.org/10.3324/haematol.2019.216648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193482PMC
May 2020

The mesenchymal niche in MDS.

Blood 2019 03 22;133(10):1031-1038. Epub 2019 Jan 22.

Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

Myelodysplastic syndrome (MDS) is characterized by bone marrow failure and a strong propensity for leukemic evolution. Somatic mutations are critical early drivers of the disorder, but the factors enabling the emergence, selection, and subsequent leukemic evolution of these "leukemia-poised" clones remain incompletely understood. Emerging data point at the mesenchymal niche as a critical contributor to disease initiation and evolution. Disrupted inflammatory signaling from niche cells may facilitate the occurrence of somatic mutations, their selection, and subsequent clonal expansion. This review summarizes the current concepts about "niche-facilitated" bone marrow failure and leukemic evolution, their underlying molecular mechanisms, and clinical implications for future innovative therapeutic targeting of the niche in MDS.
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http://dx.doi.org/10.1182/blood-2018-10-844639DOI Listing
March 2019

Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome.

Leukemia 2019 07 16;33(7):1759-1772. Epub 2019 Jan 16.

Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University, Aachen, Germany.

RPS14, CSNK1A1, and miR-145 are universally co-deleted in the 5q- syndrome, but mouse models of each gene deficiency recapitulate only a subset of the composite clinical features. We analyzed the combinatorial effect of haploinsufficiency for Rps14, Csnk1a1, and miRNA-145, using mice with genetically engineered, conditional heterozygous inactivation of Rps14 and Csnk1a1 and stable knockdown of miR-145/miR-146a. Combined Rps14/Csnk1a1/miR-145/146a deficiency recapitulated the cardinal features of the 5q- syndrome, including (1) more severe anemia with faster kinetics than Rps14 haploinsufficiency alone and (2) pathognomonic megakaryocyte morphology. Macrophages, regulatory cells of erythropoiesis and the innate immune response, were significantly increased in Rps14/Csnk1a1/miR-145/146a deficient mice as well as in 5q- syndrome patient bone marrows and showed activation of the innate immune response, reflected by increased expression of S100A8, and decreased phagocytic function. We demonstrate that Rps14/Csnk1a1/miR-145 and miR-146a deficient macrophages alter the microenvironment and induce S100A8 expression in the mesenchymal stem cell niche. The increased S100A8 expression in the mesenchymal niche was confirmed in 5q- syndrome patients. These data indicate that intrinsic defects of the 5q- syndrome hematopoietic stem cell directly alter the surrounding microenvironment, which in turn affects hematopoiesis as an extrinsic mechanism.
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http://dx.doi.org/10.1038/s41375-018-0350-3DOI Listing
July 2019

Interferon-Gamma Impairs Maintenance and Alters Hematopoietic Support of Bone Marrow Mesenchymal Stromal Cells.

Stem Cells Dev 2018 05 16;27(9):579-589. Epub 2018 Apr 16.

1 Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Academic Medical Center, University of Amsterdam , Amsterdam, Netherlands .

Bone marrow (BM) mesenchymal stromal cells (MSCs) provide microenvironmental support to hematopoietic stem and progenitor cells (HSPCs). Culture-expanded MSCs are interesting candidates for cellular therapies due to their immunosuppressive and regenerative potential which can be further enhanced by pretreatment with interferon-gamma (IFN-γ). However, it remains unknown whether IFN-γ can also influence hematopoietic support by BM-MSCs. In this study, we elucidate the impact of IFN-γ on the hematopoietic support of BM-MSCs. We found that IFN-γ increases expression of interleukin (IL)-6 and stem cell factor by human BM-MSCs. IFN-γ-treated BM-MSCs drive HSPCs toward myeloid commitment in vitro, but impair subsequent differentiation of HSPC. Moreover, IFN-γ-ARE-Del mice with increased IFN-γ production specifically lose their BM-MSCs, which correlates with a loss of hematopoietic stem cells' quiescence. Although IFN-γ treatment enhances the immunomodulatory function of MSCs in a clinical setting, we conclude that IFN-γ negatively affects maintenance of BM-MSCs and their hematopoietic support in vitro and in vivo.
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http://dx.doi.org/10.1089/scd.2017.0196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934977PMC
May 2018

Genomic and functional integrity of the hematopoietic system requires tolerance of oxidative DNA lesions.

Blood 2017 09 21;130(13):1523-1534. Epub 2017 Aug 21.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Endogenous DNA damage is causally associated with the functional decline and transformation of stem cells that characterize aging. DNA lesions that have escaped DNA repair can induce replication stress and genomic breaks that induce senescence and apoptosis. It is not clear how stem and proliferating cells cope with accumulating endogenous DNA lesions and how these ultimately affect the physiology of cells and tissues. Here we have addressed these questions by investigating the hematopoietic system of mice deficient for , a core factor in DNA translesion synthesis (TLS), the postreplicative bypass of damaged nucleotides. hematopoietic stem and progenitor cells displayed compromised proliferation, and replication stress that could be rescued with an antioxidant. The additional disruption of , essential for global-genome nucleotide excision repair (ggNER) of helix-distorting nucleotide lesions, resulted in the perinatal loss of hematopoietic stem cells, progressive loss of bone marrow, and fatal aplastic anemia between 3 and 4 months of age. This was associated with replication stress, genomic breaks, DNA damage signaling, senescence, and apoptosis in bone marrow. Surprisingly, the collapse of the bone marrow was associated with progressive mitochondrial dysfunction and consequent exacerbation of oxidative stress. These data reveal that, to protect its genomic and functional integrity, the hematopoietic system critically depends on the combined activities of repair and replication of helix-distorting oxidative nucleotide lesions by ggNER and Rev1-dependent TLS, respectively. The error-prone nature of TLS may provide mechanistic understanding of the accumulation of mutations in the hematopoietic system upon aging.
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http://dx.doi.org/10.1182/blood-2017-01-764274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620415PMC
September 2017

Persistent Hematologic Dysfunction after Peptide Receptor Radionuclide Therapy with Lu-DOTATATE: Incidence, Course, and Predicting Factors in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

J Nucl Med 2018 03 3;59(3):452-458. Epub 2017 Aug 3.

Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Peptide receptor radionuclide therapy (PRRT) may induce long-term toxicity to the bone marrow (BM). The aim of this study was to analyze persistent hematologic dysfunction (PHD) after PRRT with Lu-DOTATATE in patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs). The incidence and course of PHD were analyzed in 274 GEP NET patients from a group of 367 patients with somatostatin receptor-positive tumors. PHD was defined as diagnosis of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myeloproliferative neoplasm (MPN), MDS/MPN, or otherwise unexplained cytopenia (for >6 mo). Using data from The Netherlands Cancer Registry, the expected number of hematopoietic neoplasms (MDS, AML, MPN, and MDS/MPN) was calculated and adjusted for sex, age, and follow-up period. The following risk factors were assessed: sex, age over 70 y, bone metastasis, prior chemotherapy, prior external-beam radiotherapy, uptake on the [In-DTPA]octreotide scan, tumor load, grade 3-4 hematologic toxicity during treatment, estimated absorbed BM dose, elevated plasma chromogranin A level, baseline blood counts, and renal function. Eleven (4%) of the 274 patients had PHD after treatment with Lu-DOTATATE: 8 patients (2.9%) developed a hematopoietic neoplasm (4 MDS, 1 AML, 1 MPN, and 2 MDS/MPN) and 3 patients (1.1%) developed BM failure characterized by cytopenia and BM aplasia. The median latency period at diagnosis (or first suspicion of a PHD) was 41 mo (range, 15-84 mo). The expected number of hematopoietic neoplasms based on The Netherlands Cancer Registry data was 3.0, resulting in a relative risk of 2.7 (95% confidence interval, 0.7-10.0). No risk factors for PHD could be identified for the GEP NET patients, not even bone metastasis or estimated BM dose. Seven patients with PHD developed anemia in combination with a rise in mean corpuscular volume. The prevalence of PHD after PRRT with Lu-DOTATATE was 4% in our patient population. The median time at which PHD developed was 41 mo after the first PRRT cycle. The relative risk for developing a hematopoietic neoplasm was 2.7. No risk factors were found for the development of PHD in GEP NET patients.
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http://dx.doi.org/10.2967/jnumed.117.189712DOI Listing
March 2018

Epigenetically Aberrant Stroma in MDS Propagates Disease via Wnt/β-Catenin Activation.

Cancer Res 2017 09 6;77(18):4846-4857. Epub 2017 Jul 6.

Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

The bone marrow microenvironment influences malignant hematopoiesis, but how it promotes leukemogenesis has not been elucidated. In addition, the role of the bone marrow stroma in regulating clinical responses to DNA methyltransferase inhibitors (DNMTi) is also poorly understood. In this study, we conducted a DNA methylome analysis of bone marrow-derived stromal cells from myelodysplastic syndrome (MDS) patients and observed widespread aberrant cytosine hypermethylation occurring preferentially outside CpG islands. Stroma derived from 5-azacytidine-treated patients lacked aberrant methylation and DNMTi treatment of primary MDS stroma enhanced its ability to support erythroid differentiation. An integrative expression analysis revealed that the WNT pathway antagonist FRZB was aberrantly hypermethylated and underexpressed in MDS stroma. This result was confirmed in an independent set of sorted, primary MDS-derived mesenchymal cells. We documented a WNT/β-catenin activation signature in CD34 cells from advanced cases of MDS, where it associated with adverse prognosis. Constitutive activation of β-catenin in hematopoietic cells yielded lethal myeloid disease in a NUP98-HOXD13 mouse model of MDS, confirming its role in disease progression. Our results define novel epigenetic changes in the bone marrow microenvironment, which lead to β-catenin activation and disease progression of MDS. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600853PMC
September 2017

Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia.

Cell Stem Cell 2016 11 22;19(5):613-627. Epub 2016 Sep 22.

Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands. Electronic address:

Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system, but the underlying molecular mechanisms and relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mouse model and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signaling axis in the mesenchymal niche predicted leukemic evolution and progression-free survival in myelodysplastic syndrome (MDS), the principal leukemia predisposition syndrome. Collectively, our findings identify mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as a targetable determinant of disease outcome in human pre-leukemia.
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http://dx.doi.org/10.1016/j.stem.2016.08.021DOI Listing
November 2016

Nestin-Expressing Precursors Give Rise to Both Endothelial as well as Nonendothelial Lymph Node Stromal Cells.

J Immunol 2016 10 29;197(7):2686-94. Epub 2016 Aug 29.

Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 HZ Amsterdam, the Netherlands;

During embryogenesis, lymph nodes form through intimate interaction between lymphoid tissue inducer and lymphoid tissue organizer (LTo) cells. Shortly after birth in mice, specialized stromal cell subsets arise that organize microenvironments within the lymph nodes; however, their direct precursors have not yet been identified. In the bone marrow, mesenchymal stem cells are labeled with GFP in nestin-GFP mice, and we show that during all stages of development, nestin(+) cells are present within lymph nodes of these mice. At day of birth, both mesenchymal CD31(-) and endothelial CD31(+) LTo cells were GFP(+), and only the population of CD31(-) LTo cells contained mesenchymal precursors. These CD31(-)nestin(+) cells are found in the T and B cell zones or in close association with high endothelial venules in adult lymph nodes. Fate mapping of nestin(+) cells unambiguously revealed the contribution of nestin(+) precursor cells to the mesenchymal as well as the endothelial stromal populations within lymph nodes. However, postnatal tamoxifen induced targeting of nestin(+) cells in nes-creER mice showed that most endothelial cells and only a minority of the nonendothelial cells were labeled. Overall our data show that nestin(+) cells contribute to all subsets of the complex stromal populations that can be found in lymph nodes.
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http://dx.doi.org/10.4049/jimmunol.1501162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459591PMC
October 2016

Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes.

Haematologica 2015 Oct 16;100(10):1285-93. Epub 2015 Jul 16.

Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands

Shwachman-Diamond syndrome is a congenital bone marrow failure disorder characterized by debilitating neutropenia. The disease is associated with loss-of-function mutations in the SBDS gene, implicated in ribosome biogenesis, but the cellular and molecular events driving cell specific phenotypes in ribosomopathies remain poorly defined. Here, we established what is to our knowledge the first mammalian model of neutropenia in Shwachman-Diamond syndrome through targeted downregulation of Sbds in hematopoietic stem and progenitor cells expressing the myeloid transcription factor CCAAT/enhancer binding protein α (Cebpa). Sbds deficiency in the myeloid lineage specifically affected myelocytes and their downstream progeny while, unexpectedly, it was well tolerated by rapidly cycling hematopoietic progenitor cells. Molecular insights provided by massive parallel sequencing supported cellular observations of impaired cell cycle exit and formation of secondary granules associated with the defect of myeloid lineage progression in myelocytes. Mechanistically, Sbds deficiency activated the p53 tumor suppressor pathway and induced apoptosis in these cells. Collectively, the data reveal a previously unanticipated, selective dependency of myelocytes and downstream progeny, but not rapidly cycling progenitors, on this ubiquitous ribosome biogenesis protein, thus providing a cellular basis for the understanding of myeloid lineage biased defects in Shwachman-Diamond syndrome.
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http://dx.doi.org/10.3324/haematol.2015.131573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591760PMC
October 2015

Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow.

J Exp Med 2015 May 27;212(5):759-74. Epub 2015 Apr 27.

Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02215 Harvard Stem Cell Institute, Cambridge, MA 02215 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02215

Production of the cells that ultimately populate the thymus to generate α/β T cells has been controversial, and their molecular drivers remain undefined. Here, we report that specific deletion of bone-producing osteocalcin (Ocn)-expressing cells in vivo markedly reduces T-competent progenitors and thymus-homing receptor expression among bone marrow hematopoietic cells. Decreased intrathymic T cell precursors and decreased generation of mature T cells occurred despite normal thymic function. The Notch ligand DLL4 is abundantly expressed on bone marrow Ocn(+) cells, and selective depletion of DLL4 from these cells recapitulated the thymopoietic abnormality. These data indicate that specific mesenchymal cells in bone marrow provide key molecular drivers enforcing thymus-seeding progenitor generation and thereby directly link skeletal biology to the production of T cell-based adaptive immunity.
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http://dx.doi.org/10.1084/jem.20141843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419348PMC
May 2015

Transmembrane Inhibitor of RICTOR/mTORC2 in Hematopoietic Progenitors.

Stem Cell Reports 2014 Nov 25;3(5):832-40. Epub 2014 Sep 25.

Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address:

Central to cellular proliferative, survival, and metabolic responses is the serine/threonine kinase mTOR, which is activated in many human cancers. mTOR is present in distinct complexes that are either modulated by AKT (mTORC1) or are upstream and regulatory of it (mTORC2). Governance of mTORC2 activity is poorly understood. Here, we report a transmembrane molecule in hematopoietic progenitor cells that physically interacts with and inhibits RICTOR, an essential component of mTORC2. Upstream of mTORC2 (UT2) negatively regulates mTORC2 enzymatic activity, reducing AKT(S473), PKCα, and NDRG1 phosphorylation and increasing FOXO transcriptional activity in an mTORC2-dependent manner. Modulating UT2 levels altered animal survival in a T cell acute lymphoid leukemia (T-ALL) model that is known to be mTORC2 sensitive. These studies identify an inhibitory component upstream of mTORC2 in hematopoietic cells that can reduce mortality from NOTCH-induced T-ALL. A transmembrane inhibitor of mTORC2 may provide an attractive target to affect this critical cell regulatory pathway.
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http://dx.doi.org/10.1016/j.stemcr.2014.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235746PMC
November 2014

Disease progression in myelodysplastic syndromes: do mesenchymal cells pave the way?

Cell Stem Cell 2014 Jun;14(6):695-7

Department of Hematology, Erasmus MC Cancer Institute, and Erasmus Stem Cell Institute, Faculty Building Rm Ee-1393, dr. Molewaterplein 50, 3015GE, Rotterdam, The Netherlands. Electronic address:

Early events driving the initiation and evolution of neoplasms remain poorly defined but involvement of an instructive or permissive niche has been implicated. In this issue of Cell Stem Cell, Medyouf et al. (2014) provide insights into the role of the niche in myelodysplastic syndromes, the principle preleukemic disorder of the hematopoietic system.
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http://dx.doi.org/10.1016/j.stem.2014.05.010DOI Listing
June 2014

Myelodysplastic syndromes: revisiting the role of the bone marrow microenvironment in disease pathogenesis.

Int J Hematol 2012 Jan 6;95(1):17-25. Epub 2012 Jan 6.

Department of Hematology and Erasmus Stem Cell Institute, Erasmus University Medical Center, Faculty Building Rm Ee-1393, dr. Molewaterplein 50, 3015GE Rotterdam, The Netherlands.

Myelodysplastic syndromes are a heterogeneous group of diseases characterized by ineffective hematopoiesis and the propensity to leukemic transformation. Their pathogenesis is complex and likely depends on interplay between aberrant hematopoietic cells and their microenvironment. How niche cells play a role in disease evolution is poorly defined, but the delineation of the hematopoietic stem cell niche and the ability to interrogate its role in hematopoietic disease in animal models have furthered our insights in recent years. The data support a view in which the microenvironment can play an active role in the evolution of myelodysplasia and myeloproliferative disorders, thus providing further rationale to explore therapeutic targeting of mesenchymal-hematopoietic interactions in these diseases.
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http://dx.doi.org/10.1007/s12185-011-1001-xDOI Listing
January 2012

Niche contributions to oncogenesis: emerging concepts and implications for the hematopoietic system.

Haematologica 2011 Jul 1;96(7):1041-8. Epub 2011 Apr 1.

Erasmus University Medical Center, Department of Hematology and Erasmus Stem Cell Institute, Faculty Building, Rm Ee-1393, Dr. Molewaterplein 50, 3015GE Rotterdam, The Netherlands.

The field of hematopoietic oncology has traditionally focused on the study of hematopoietic cell autonomous genetic events in an effort to understand malignant transformation and develop therapeutics. Although highly rewarding in both aspects, this cell autonomous approach has failed to fully satisfy our need to understand tumor cell behavior and related clinical observations. In recent years, it has been increasingly recognized that the tumor microenvironment plays a pivotal role in cancer initiation and progression. This review will discuss recent experimental evidence in support of this view derived from investigations in both epithelial and hematopoietic systems. Based on this, conceptual views and therapeutic implications will be provided on the emerging role of the bone marrow microenvironment in leukemogenesis.
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http://dx.doi.org/10.3324/haematol.2010.028035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128224PMC
July 2011

Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia.

Nature 2010 Apr 21;464(7290):852-7. Epub 2010 Mar 21.

Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School CPZN, USA.

Mesenchymal cells contribute to the 'stroma' of most normal and malignant tissues, with specific mesenchymal cells participating in the regulatory niches of stem cells. By examining how mesenchymal osteolineage cells modulate haematopoiesis, here we show that deletion of Dicer1 specifically in mouse osteoprogenitors, but not in mature osteoblasts, disrupts the integrity of haematopoiesis. Myelodysplasia resulted and acute myelogenous leukaemia emerged that had acquired several genetic abnormalities while having intact Dicer1. Examining gene expression altered in osteoprogenitors as a result of Dicer1 deletion showed reduced expression of Sbds, the gene mutated in Schwachman-Bodian-Diamond syndrome-a human bone marrow failure and leukaemia pre-disposition condition. Deletion of Sbds in mouse osteoprogenitors induced bone marrow dysfunction with myelodysplasia. Therefore, perturbation of specific mesenchymal subsets of stromal cells can disorder differentiation, proliferation and apoptosis of heterologous cells, and disrupt tissue homeostasis. Furthermore, primary stromal dysfunction can result in secondary neoplastic disease, supporting the concept of niche-induced oncogenesis.
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http://dx.doi.org/10.1038/nature08851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422863PMC
April 2010

Divided within: heterogeneity within adult stem cell pools.

Cell 2008 Dec;135(6):1006-8

Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

In this issue, Wilson et al. (2008) demonstrate that there are two functional subsets of hematopoietic stem cells that have distinctive kinetics of cell cycling. They present evidence that cells may transition between the two kinetic states, establishing one subpopulation that is ready to proliferate and another that is a deeply quiescent reserve.
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http://dx.doi.org/10.1016/j.cell.2008.11.034DOI Listing
December 2008

Evolving concepts on the microenvironmental niche for hematopoietic stem cells.

Curr Opin Hematol 2008 Jul;15(4):301-6

Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Purpose Of Review: The hematopoietic stem cell niche is critical for the maintenance and proliferation of hematopoietic stem cells and, as such, is not only essential for steady-state hematopoiesis but may also be relevant to hematologic disease. The present review discusses recent advances in the understanding of interactions within the niche, its potential role in disease pathogenesis and models of its use as a therapeutic target.

Recent Findings: Recent studies have continued to provide important insights into the cellular and molecular components constituting the hematopoietic stem cell niche. Niche interactions have been shown to be involved in the pathogenesis of hematologic disease in animal models. Molecular components of the niche involved in these interactions have been identified, and proof of principle that their manipulation can result in therapeutic benefit is available. Finally, pharmacologic manipulation of the niche is now being tested in stem cell-based therapies.

Summary: Increasing insights into the molecular architecture of the hematopoietic stem cell niche have led to the exploitation of the niche as a target in stem cell therapies and offer the prospect of niche-targeted therapy as a new treatment modality in hematologic disease.
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http://dx.doi.org/10.1097/MOH.0b013e328303e14cDOI Listing
July 2008

ABCB1 modulation does not circumvent drug extrusion from primitive leukemic progenitor cells and may preferentially target residual normal cells in acute myelogenous leukemia.

Clin Cancer Res 2006 Jun;12(11 Pt 1):3452-8

Department of Hematology and Central Hematology Laboratory, University Medical Center Nijmegen, Nijmegen, The Netherlands.

Purpose: Acute myelogenous leukemia (AML) is a disease originating from normal hematopoietic CD34+ CD38- progenitor cells. Modulation of the multidrug ATP-binding cassette transporter ABCB1 has not resulted in improved outcome in AML, raising the question whether leukemic CD34+ CD38- cells are targeted by this strategy.

Experimental Design: ABCB1-mediated transport in leukemic CD34+ CD38- cells compared with their normal counterparts was assessed by quantitating the effect of specific ABCB1 modulators (verapamil and PSC-833) on mitoxantrone retention [defined as efflux index (EI), intracellular mitoxantrone fluorescence intensity in the presence/absence of inhibitor].

Results: ABCB1 was the major drug transporter in CD34+ CD38- cells in normal bone marrow (n = 16), as shown by the abrogation of mitoxantrone extrusion by ABCB1 modulators (EI, 1.99 +/- 0.08). Surprisingly, ABCB1-mediated drug extrusion was invariably reduced in CD34+ CD38- cells in AML (n = 15; EI, 1.21 +/- 0.05; P < 0.001), which resulted in increased intracellular mitoxantrone retention in these cells (mitoxantrone fluorescence intensity, 4.54 +/- 0.46 versus 3.08 +/- 0.23; P = 0.004). Active drug extrusion from these cells occurred in the presence of ABCB1 modulators in the majority of samples, pointing in the direction of redundant drug extrusion mechanisms. Residual normal CD34+ CD38- cells could be identified by their conserved ABCB1-mediated extrusion capacity.

Conclusion: ABCB1-mediated drug extrusion is reduced in leukemic CD34+ CD38- progenitor cells compared with their residual normal counterparts. Redundant drug transport mechanisms confer mitoxantrone transport from leukemic progenitors. These data argue that ABCB1 modulation is not an effective strategy to circumvent drug extrusion from primitive leukemic progenitor cells and may preferentially target residual normal progenitors in AML.
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http://dx.doi.org/10.1158/1078-0432.CCR-05-1945DOI Listing
June 2006

Impaired breast cancer resistance protein mediated drug transport in plasma cells in multiple myeloma.

Leuk Res 2005 Dec;29(12):1455-8

Department of Hematology, University Medical Center Nijmegen, St. Radboud, The Netherlands.

The breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding-cassette transporter involved in the transport of drugs used in the treatment of multiple myeloma (MM). Its expression, function and clinical significance in MM, however, are unknown. We report that BCRP is preferentially expressed and functionally active in normal plasma cells but that its function is significantly impaired in plasma cells in newly diagnosed MM. The data presented argue against a role for BCRP in primary drug resistance in MM and the utilisation as a molecular target as such but warrant research into its (patho)physiological role in normal and malignant plasma cells.
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http://dx.doi.org/10.1016/j.leukres.2005.04.013DOI Listing
December 2005

Breast cancer resistance protein in drug resistance of primitive CD34+38- cells in acute myeloid leukemia.

Clin Cancer Res 2005 Mar;11(6):2436-44

Department of Hematology and Central Hematology Laboratory, University Medical Center Nijmegen, St. Radboud, 6500 HB Nijmegen, the Netherlands.

Purpose: Acute myeloid leukemia (AML) is considered a stem cell disease. Incomplete chemotherapeutic eradication of leukemic CD34+38- stem cells is likely to result in disease relapse. The purpose of this study was to investigate the role of the breast cancer resistance protein (BCRP/ATP-binding cassette, subfamily G, member 2) in drug resistance of leukemic stem cells and the effect of its modulation on stem cell eradication in AML.

Experimental Design: BCRP expression (measured flow-cytometrically using the BXP21 monoclonal antibody) and the effect of its modulation (using the novel fumitremorgin C analogue KO143) on intracellular mitoxantrone accumulation and in vitro chemosensitivity were assessed in leukemic CD34+38- cells.

Results: BCRP was preferentially expressed in leukemic CD34+38- cells and blockage of BCRP-mediated drug extrusion by the novel fumitremorgin C analogue KO143 resulted in increased intracellular mitoxantrone accumulation in these cells in the majority of patients. This increase, however, was much lower than in the mitoxantrone-resistant breast cancer cell line MCF7-MR and significant drug extrusion occurred in the presence of BCRP blockage due to the presence of additional drug transport mechanisms, among which ABCB1 and multiple drug resistance protein. In line with these findings, selective blockage of BCRP by KO143 did not enhance in vitro chemosensitivity of leukemic CD34+38- cells.

Conclusions: These results show that drug extrusion from leukemic stem cells is mediated by the promiscuous action of BCRP and additional transporters. Broad-spectrum inhibition, rather than modulation of single mechanisms, is therefore likely to be required to circumvent drug resistance and eradicate leukemic stem cells in AML.
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http://dx.doi.org/10.1158/1078-0432.CCR-04-0212DOI Listing
March 2005

Quantitative assessment of gene expression in highly purified hematopoietic cells using real-time reverse transcriptase polymerase chain reaction.

Exp Hematol 2002 May;30(5):481-7

Department of Hematology and Central Hematology Laboratory, University Medical Center Nijmegen, Nijmegen, The Netherlands.

Objective: Quantitative assessment of gene expression in stem cells is essential for understanding the molecular events underlying normal and malignant hematopoiesis. The aim of the present study was to develop a method for precise quantitation of gene expression in small subsets of highly purified CD34(+)CD38(-) stem cell populations.

Materials And Methods: Real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to quantitate housekeeping and drug resistance gene expression in cDNA obtained from 300 CD34(+)CD38(-) cells without cDNA amplification or nested PCR techniques.

Results: Validation experiments in cell lines showed efficient, representative and reproducible gene amplification using 300-cell real-time quantitative RT-PCR. Sensitivity was confirmed in dilutional experiments and by detection of the low-copy gene PBGD. GAPDH was found to be a useful reference gene in normal and leukemic CD34(+)CD38(-) cells. In contrast, 18S rRNA content varied 100-fold to 1000-fold in these populations. Moreover, expression of 18S rRNA was significantly lower in leukemic CD34(+)CD38(+) cells compared to normal CD34(+)CD38(+) cells (p = 0.002). Expression of MDR-1 (18-fold, p < 0.0005), MRP-1 (3.8-fold, p < 0.05), and LRP (1.8-fold, NS) was higher in normal CD34(+)CD38(-) compared to CD34(+)CD38(+) cells.

Conclusions: Real-time quantitative RT-PCR is a valuable tool for precise quantitation of gene expression in small subsets of hematopoietic cells. Using this method, we showed the inappropriateness of 18S as a reference gene in these progenitors and the down-regulation of drug-resistance-related genes early in hematopoiesis.
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http://dx.doi.org/10.1016/s0301-472x(02)00787-7DOI Listing
May 2002