Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia

Cahu, Xavier; Calvo, Julien; Poglio, Sandrine; Prade, Naïs; Colsch, Benoît; Arcangeli, Marie-Laure; Leblanc, Thierry; Petit, Arnaud; Baleydier, Fréderic; Baruchel, André; Landman‐Parker, Judith; Junot, Christophe; Larghero, Jérôme; Ballerini, Paola; Delabesse, Éric; Uzan, Benjamin; Pflumio, Françoise

doi:10.1182/bloodadvances.2017004960

Cited by 47 publications

(46 citation statements)

References 36 publications

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“…Additionally, daunorubicin is another important chemotherapeutic for leukemias and adipocytes enhance survival of acute lymphoblastic leukemia cells by secreting factors which protect the tumor cells from oxidative stress, as well as by accumulating and inactivating significant amounts of daunorubicin [103, 104]. Lastly, human T-cell acute lymphoblastic leukemia (T-ALL) cancer cells transplanted into mice accumulate in gonadal adipose tissue of mice and adopt enhanced chemoresistance profiles similar to T-ALL cells in bone marrow sites rich in adipocytes, and adipose T-ALL cells furthermore became more resistant to vincristine when co-cultured with adipocytes in vitro [105]. These studies further highlight the dynamic nature of adipocytes and interaction with other cells beyond metabolism.…”

Section: Antiretroviral Therapy and Adipose Tissuementioning

confidence: 99%

HIV Persistence in Adipose Tissue Reservoirs

Couturier

Lewis

2018

Curr HIV/AIDS Rep

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Memory CD4 T cells and macrophages, the major host cells for HIV, accumulate in adipose tissue during HIV/SIV infection of humans and rhesus macaques. Whereas HIV and SIV proviral DNA is detectable in CD4 T cells of multiple fat depots in virtually all infected humans and monkeys examined, viral RNA is less frequently detected, and infected macrophages may be less prevalent in adipose tissue. However, based on viral outgrowth assays, adipose-resident CD4 T cells are latently infected with virus that is replication-competent and infectious. Additionally, adipocytes interact with CD4 T cells and macrophages to promote immune cell activation and inflammation which may be supportive for HIV persistence. Antiviral effector cells, such as CD8 T cells and NK/NKT cells, are abundant in adipose tissue during HIV/SIV infection and typically exceed CD4 T cells, whereas B cells are largely absent from adipose tissue of humans and monkeys. Additionally, CD8 T cells in adipose tissue of HIV patients are activated and have a late differentiated phenotype, with unique TCR clonotypes of less diversity relative to blood CD8 T cells. With respect to the distribution of antiretroviral drugs in adipose tissue, data is limited, but there may be class-specific penetration of fat depots. The trafficking of infected immune cells within adipose tissues is a common event during HIV/SIV infection of humans and monkeys, but the virus may be mostly transcriptionally dormant. Viral replication may occur less in adipose tissue compared to other major reservoirs, such as lymphoid tissue, but replication competence and infectiousness of adipose latent virus are comparable to other tissues. Due to the ubiquitous nature of adipose tissue, inflammatory interactions among adipocytes and CD4 T cells and macrophages, and selective distribution of antiretroviral drugs, the sequestration of infected immune cells within fat depots likely represents a major challenge for cure efforts.

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Section: Antiretroviral Therapy and Adipose Tissuementioning

confidence: 99%

HIV Persistence in Adipose Tissue Reservoirs

Couturier

Lewis

2018

Curr HIV/AIDS Rep

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“…In contrast to MAT's supportive function of normal hematopoiesis during leukemia, its role in leukemia development is controversial and might be lineage specific. Thus, MAT was found to negatively affect T-ALL proliferation in vitro and in vivo thereby mediating chemoresistance [60]. On the other hand, MAT supported the survival and proliferation of AML blasts from patients [61] by hijacking the metabolism of adipocytes to induce free fatty acid release via activation of lipolysis [61].…”

Section: Mat In Malignant Hematopoiesismentioning

confidence: 99%

Adipocytes in hematopoiesis and acute leukemia: friends, enemies, or innocent bystanders?

Zinngrebe¹,

Debatin²,

Fischer‐Posovszky³

2020

Leukemia

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The bone marrow is home to well-balanced normal hematopoiesis, but also the stage of leukemia’s crime. Marrow adipose tissue (MAT) is a unique and versatile component of the bone marrow niche. While the importance of MAT for bone health has long been recognized, its complex role in hematopoiesis has only recently gained attention. In this review article we summarize recent conceptual advances in the field of MAT research and how these developments impact our understanding of MAT regulation of hematopoiesis. Elucidating routes of interaction and regulation between MAT and cells of the hematopoietic system are essential to pinpoint vulnerable processes resulting in malignant transformation. The concept of white adipose tissue contributing to cancer development and progression on the cellular, metabolic, and systemic level is generally accepted. The role of MAT in malignant hematopoiesis, however, is controversial. MAT is very sensitive to changes in the patient’s metabolic status hampering a clear definition of its role in different clinical situations. Here, we discuss future directions for leukemia research in the context of metabolism-induced modifications of MAT and other adipose tissues and how this might impact on leukemia cell survival, proliferation, and antileukemic therapy.

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“…The discovery of the micro environmental effect on the fate of stem cells (7)(8)(9)(10)(11)(12)(13) gave rise to the concept of "quiescent"-now widely considered to be a "dormant-like cell" in the bone marrow (14,15). Studies on the interplay between microenvironment and cancer proliferation have suggested additional prognostic factors such as cell cycle and metabolismrelated chemo-resistant heterogeneity in cancers (16)(17)(18). In T-cell acute lymphoblastic leukemia (T-ALL), for example, various bone marrow niches differentially protect T-ALL cells from chemotherapy by inducing quiescence (18).…”

Section: Introductionmentioning

confidence: 99%

“…Studies on the interplay between microenvironment and cancer proliferation have suggested additional prognostic factors such as cell cycle and metabolismrelated chemo-resistant heterogeneity in cancers (16)(17)(18). In T-cell acute lymphoblastic leukemia (T-ALL), for example, various bone marrow niches differentially protect T-ALL cells from chemotherapy by inducing quiescence (18).…”

Section: Introductionmentioning

confidence: 99%

“…Single cell RNA-seq profiling can reveal gene expression variation between individual cells with important roles in subpopulation dynamics (26)(27)(28); for example in the late relapses of patients with Ewing sarcoma (EWS) (29). Many studies have demonstrated heterogeneity within cell populations (30)(31)(32)(33), and single-cell RNA-seq technology can provide a promising and unbiased approach to unravel the key molecular programs leading to cancer heterogeneity at cellular resolution (14)(15)(16)(17)(18)34).…”

Section: Introductionmentioning

confidence: 99%

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Single-cell RNA Profiling Identifies Diverse Cellular Responses to EWSR1-FLI1 Down-regulation in Ewing Sarcoma

Khoogar

Lawlor

Ignatius

et al. 2019

Preprint

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Single-cell analyses provide insight into time dependent behaviors in response to dynamic changes of oncogene expression. We developed an unbiased approach to study gene expression variation using a model of cellular dormancy induced via EWSR1-FLI1 down-regulation in Ewing sarcoma (EWS) cells. We propose that variation in the expression of EWSR1-FLI1 over time determines cellular responses. Cell state and functions were assigned using random forest feature selection in combination with machine learning. Notably, three distinct expression profiles were uncovered contributing to Ewing sarcoma cell heterogeneity. Our predictive model identified ~1% cells in a dormant-like state and ~2-4% with higher stem-like and neural stem-like features in an exponentially proliferating EWS cell line and EWS xenografts. Following oncogene knockdown, cells re-entering the proliferative cycle have greater stem-like properties, whereas for those remaining quiescent, FAM134B-dependent dormancy provides a survival mechanism. We also show cell cycle heterogeneity related to EWSR1-FLI1 expression as an independent feature driving cancer heterogeneity, and drug resistance.SIGNIFICANCE We show that time-dependent changes induced by suppression of oncogenic EWSR1-FLI1 induces dormancy, with different subpopulation dynamics, including stem-like characteristics and prolonged dormancy. Cells with these characteristics are identified in exponentially growing cell populations and confer drug resistance, and could potentially contribute to metastasis or late recurrence in patients.

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Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia

Abstract: Key Points BM niches differentially support T-ALL. BM niches differentially protect T-ALL cells from chemotherapy.

Cited by 47 publications

References 36 publications

HIV Persistence in Adipose Tissue Reservoirs

HIV Persistence in Adipose Tissue Reservoirs

Adipocytes in hematopoiesis and acute leukemia: friends, enemies, or innocent bystanders?

Single-cell RNA Profiling Identifies Diverse Cellular Responses to EWSR1-FLI1 Down-regulation in Ewing Sarcoma

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