Bone Morphogenetic Protein 4 Contributes to the Maintenance of Primitive Cord Blood Hematopoietic Progenitors in an Ex Vivo Stroma-Noncontact Co-Culture System

Hutton, Jonathon F.; Rozenkov, Vladislav; Khor, Fiona; D’Andrea, Richard J.; Lewis, Ian D.

doi:10.1089/scd.2006.15.805

Cited by 22 publications

(10 citation statements)

References 53 publications

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“…12,13 These molecules are naturally produced by stromal cells, megakaryocytes, and platelets. 12 In humans, BMP2, BMP4, and BMP7 regulate the proliferation, maintenance, 14 clonogenicity, and repopulating activities of immature cell populations. 9,15 In the absence of erythropoietin, BMP2 induces cell commitment and differentiation toward erythropoiesis, 16 whereas BMP4 sustains SC maintenance and megakaryocytopoiesis.…”

Section: Introductionmentioning

confidence: 99%

Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression

Laperrousaz

Jeanpierre

Sagorny

et al. 2013

Blood

101

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Key Points• In CML, early alterations of the BMP pathway are involved in the survival of hypersensitive LSCs and the expansion of myeloid progenitors.• The leukemic niche provides higher concentrations of BMP2 and BMP4 that fuel a permanent and autonomous pool of leukemic progenitors.Leukemic stem cells in chronic phase chronic myelogenous leukemia (CP-CML) are responsible for disease persistence and eventual drug resistance, most likely because they survive, expand, and are sustained through interactions with their microenvironment. Bone morphogenetic proteins 2 (BMP2) and 4 (BMP4) regulate the fate and proliferation of normal hematopoietic stem cells, as well as interactions with their niche. We show here that the intrinsic expression of members of the BMP response pathway are deregulated in CML cells with differences exhibited in mature (CD34 2 ) and immature (CD34 1 ) compartments. These changes are accompanied by altered functional responses of primitive leukemic cells to BMP2 and BMP4 and strong increases in soluble BMP2 and BMP4 in the CML bone marrow. Using primary cells and a cell line mimicking CP-CML, we found that myeloid progenitor expansion is driven by the exposure of immature cells overexpressing BMP receptor Ib to BMP2 and BMP4. In summary, we demonstrate that deregulation of intracellular BMP signaling in primary CP-CML samples corrupts and amplifies their response to exogenous BMP2 and BMP4, which are abnormally abundant within the tumor microenvironment. These results provide new insights with regard to leukemic stem cell biology and suggest possibilities for the development of novel therapeutic tools specifically targeting the CML niche. (Blood. 2013;122(23):3767-3777) IntroductionChronic myelogenous leukemia (CML) likely arises from a stem cell (SC) transformation induced by the formation of the BCR-ABL oncogene. Without treatment, the disease evolves to an inexorable fatal blast crisis. Until recently, imatinib has become the gold standard for chronic phase (CP)-CML care.1 However, some discrete Philadelphia-positive (Ph 1 ) leukemic SCs (LSCs) may be insensitive to tyrosine kinase inhibitors (TKIs) 2-4 and, therefore, sustain detectable disease for many years. None of the therapeutic agents available to date seem to eradicate the undifferentiated BCR-ABL 1 cells that serve as a reservoir for additional oncogenic events leading to disease progression, 2,4-6 and they require continued treatment. 7,8 Therefore, CML represents a unique model to study LSC biology and to elucidate some of the mechanisms of therapeutic resistance.Complete elimination of CML clones has rarely been achieved by TKIs because of the development of a variety of cell-intrinsic and cell-extrinsic protective mechanisms. Extrinsic mechanisms are supported by the bone marrow (BM) microenvironment, the so-called "leukemic niche." Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-b superfamily and regulate hematopoietic SC fate both directly at various stages of SC differentiation 9-11 and indir...

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Section: Introductionmentioning

confidence: 99%

Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression

Laperrousaz

Jeanpierre

Sagorny

et al. 2013

Blood

101

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“…16 In particular, in Xenopus embryos, ectopic BMP4 expression induces several hematopoietic genes. 11,16 In humans, BMP2, BMP4, and BMP7 regulate the proliferation, maintenance, 17 clonogenicity, and repopulating capacity of CD34 ϩ CD38 Ϫ primitive hematopoietic populations. 12 BMP2 and BMP4, either alone or in combination with activin A, regulate erythropoiesis in various models.…”

Section: Introductionmentioning

confidence: 99%

BMP4 regulation of human megakaryocytic differentiation is involved in thrombopoietin signaling

Jeanpierre

Nicolini

Kaniewski

et al. 2008

Blood

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Activin A, BMP2, and BMP4, 3 members of the transforming growth factor-␤ family, are involved in the regulation of hematopoiesis. Here, we explored the role of these molecules in human megakaryopoiesis using an in vitro serum-free assay. Our results highlight for the first time that, in the absence of thrombopoietin, BMP4 is able to induce CD34 ؉ progenitor differentiation into megakaryocytes through all stages. Although we have previously shown that activin A and BMP2 are involved in erythropoietic commitment, these molecules have no effect on human megakaryopoietic engagement and differentiation. Using signaling pathway-specific inhibitors, we show that BMP4, like thrombopoietin, exerts its effects on human megakaryopoiesis through the JAK/STAT and mTor path-

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“…Morphogens of the hedgehog family, namely Sonic and Indian hedgehogs, are able to support ex vivo expansion of human NOD/SCID repopulating cells (Bhardwaj et al, 2001;Kobune et al, 2004), despite the fact that in vivo Hedgehog signaling seems to not be necessary for adult murine hematopoietic stem cell function (Hofmann et al, 2009). BMP4, a member of BMP superfamily, is a critical component of the hematopoietic niche that regulates both HSC number and function (Goldman et al, 2009), and is able to expand NOD/SCID-repopulating cells in culture (Hutton et al, 2006).…”

Section: Expansion and Selection Of Genetically Modified Hscs Ex Vivomentioning

confidence: 99%

Gene Therapy of Hematopoietic and Immune Systems: Current State and Perspectives

Савватеева¹,

Rozov²,

Belyavsky³

2012

Advances in Hematopoietic Stem Cell Research

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Bone Morphogenetic Protein 4 Contributes to the Maintenance of Primitive Cord Blood Hematopoietic Progenitors in an Ex Vivo Stroma-Noncontact Co-Culture System

Cited by 22 publications

References 53 publications

Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression

Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression

BMP4 regulation of human megakaryocytic differentiation is involved in thrombopoietin signaling

Gene Therapy of Hematopoietic and Immune Systems: Current State and Perspectives

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