AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth

Battula, Venkata Lokesh; Le, Phuong M.; Sun, Jerry Chih‐Yuan; Nguyen, Khoa; Yuan, Bin; Zhou, Xi; Sonnylal, Sonali; McQueen, Teresa; Ruvolo, Vivian; Michel, Keith A.; Ling, Xiaoyang; Jácamo, Rodrigo; Shpall, Elizabeth J.; Wang, Zhiqiang; Rao, Arvind; Alatrash, Gheath; Konopleva, Marina; Davis, R. Eric; Harrington, Melvyn A.; Cahill, Catherine W.; Bueso-Ramos, Carlos; Andreeff, Michael

doi:10.1172/jci.insight.90036

Cited by 105 publications

(138 citation statements)

References 47 publications

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“…In contrast to these findings, a study using a congenic model of CML found direct induction of osteoblastic expansion through differentiation of endosteal MSCs, leading to fibrosis and thickening of the trabecular wall through chemokine driven TGF‐β, Notch, and inflammatory signaling pathways, and subsequently affecting normal HSC retention and maintenance . Another recent study demonstrated that AML blasts preferentially induce osteolineage induction of MSCs, while blocking adipogenic differentiation in transplanted mice . This manipulation of differentiation is accomplished through the increased secretion of BMP2 and BMP4 in the AML niche, whereby expanded osteoblastic cells overexpress connective tissue growth factor which increases leukemic engraftment.…”

Section: Leukemia‐mediated Changes To Stromal Composition and Functionmentioning

confidence: 97%

Concise Review: Adaptation of the Bone Marrow Stroma in Hematopoietic Malignancies: Current Concepts and Models

2018

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The bone marrow stroma maintains hematopoiesis and coordinately regulates regenerative responses through dynamic interactions with hematopoietic stem and progenitor cells. Recent studies indicate that stromal components in the bone marrow of leukemia patients undergo a process of successive adaptation that in turn exerts dramatic effects on the hematopoietic stem cell compartment and promotes leukemic drug resistance. Therefore, functional changes in discrete marrow stromal populations can be considered an aspect of leukemia biogenesis in that they create an aberrant, self-reinforcing microenvironment. In this review, we will describe the current understanding of the remodeling of the hematopoietic stem cell niche following invasion by leukemia cells. We place emphasis on existing evidence of how mesenchymal stem cells and their progeny facilitate neoplastic growth and describe available models and analytical techniques to understand the conversion of the niche toward disease persistence. STEM CELLS 2018;36:304-312 SIGNIFICANCE STATEMENTThere is increasing awareness that the bone marrow microenvironment is a critical contributor to therapeutic resistance and relapse progression in hematological malignancies. Experimental evidence discussed herein highlights key aspects of the stromal conversion by leukemia and the resulting aberrant signaling within the niche. This article discusses the advantages and limitations of available experimental model system and emphasizes open scientific questions and opportunities.

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Section: Leukemia‐mediated Changes To Stromal Composition and Functionmentioning

confidence: 97%

Concise Review: Adaptation of the Bone Marrow Stroma in Hematopoietic Malignancies: Current Concepts and Models

2018

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“…Another report found that AML cells appear to induce osteogenic differentiation, but inhibit adipocytic differentiation of MSCs. Here, induction of osteogenic differentiation was thought to be due to activation of Smad-1/5 signaling in MSCs by bone morphogenetic proteins (BMPs) derived from AML cells, leading to an increase in preosteoblastic cells in the leukemic niche (Battula et al, 2017). In myeloproliferative neoplasia (MPN), the endosteal niche is remodeled into a leukemic niche through the stimulation of mesenchymal stromal cells and the generation of functionally abnormal osteoblastic cells; here, thrombopoietin, CCL3 and direct cell-cell interactions were shown to promote the expansion of osteoblastic cells, and TGF-β, Notch and inflammatory signaling were shown to be involved in niche remodeling (Schepers et al, 2013).…”

Section: Alteration Of the Bmm By Malignant Hematopoietic Cellsmentioning

confidence: 99%

The bone marrow microenvironment in health and disease at a glance

Kumar

Godavarthy

Krause

2018

Journal of Cell Science

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The bone marrow microenvironment (BMM) is the 'domicile' of hematopoietic stem cells, as well as of malignant processes that can develop there. Multiple and complex interactions with the BMM influence hematopoietic stem cell (HSC) physiology, but also the pathophysiology of hematological malignancies. Reciprocally, hematological malignancies alter the BMM, in order to render it more hospitable for malignant progression. In this Cell Science at a Glance article and accompanying poster, we highlight concepts of the normal and malignant hematopoietic stem cell niches. We present the intricacies of the BMM in malignancy and provide approaches for targeting the interactions between malignant cells and their BMM. This is done in an effort to augment existing treatment strategies in the future.

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“…A parallel mechanism of IL‐1β‐mediated damage of neuronal cells by JAK2V617F hematopoietic cells has been reported as well . Similarly, AML cells unleash pleomorphic effects on osteolineage cells, adipocytes, endothelial cells, and sympathetic neurons, in turn promoting clonal expansion, skewing MSC differentiation, and downregulating factors required for normal HSPC function (e.g., CXCL12, SCF). Last, in a co‐culture system, MDS hematopoietic cells induce transcriptional changes in mesenchymal cells that facilitate engraftment and disease progression in a murine xenograft model .…”

Section: Deranged Hematopoiesismentioning

confidence: 78%

Bone Marrow Micro‐Environment in Normal and Deranged Hematopoiesis: Opportunities for Regenerative Medicine and Therapies

2018

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Various cell types cooperate to create a highly organized and dynamic micro-environmental niche in the bone marrow. Over the past several years, the field has increasingly recognized the critical roles of the interplay between bone marrow environment and hematopoietic cells in normal and deranged hematopoiesis. These advances rely on several new technologies that have allowed us to characterize the identity and roles of these niches in great detail. Here, we review the progress of the last several years, list some of the outstanding questions in the field and propose ways to target the diseased environment to better treat hematologic diseases. Understanding the extrinsic regulation by the niche will help boost hematopoiesis for regenerative medicine. Based on natural development of hematologic malignancies, we propose that combinatory targeting the niche and hematopoietic intrinsic mechanisms in early stages of hematopoietic malignancies may help eliminate minimal residual disease and have the highest efficacy.

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AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth

Cited by 105 publications

References 47 publications

Concise Review: Adaptation of the Bone Marrow Stroma in Hematopoietic Malignancies: Current Concepts and Models

Concise Review: Adaptation of the Bone Marrow Stroma in Hematopoietic Malignancies: Current Concepts and Models

The bone marrow microenvironment in health and disease at a glance

Bone Marrow Micro‐Environment in Normal and Deranged Hematopoiesis: Opportunities for Regenerative Medicine and Therapies

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