Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia

Diana Passaro; Alessandro Di Tullio; Ander Abarrategi; Kevin Rouault-Pierre; Katie Foster; Linda Ariza-McNaughton; Beatriz Montaner; Probir Chakravarty; Leena Bhaw; Giovanni Diana; François Lassailly; John Gribben; Dominique Bonnet

doi:10.1016/j.ccell.2017.08.001

Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia

Diana Passaro, Alessandro Di Tullio, Ander Abarrategi, Kevin Rouault-Pierre, Katie Foster, Linda Ariza-McNaughton, Beatriz Montaner, Probir Chakravarty, Leena Bhaw, Giovanni Diana, François Lassailly, John Gribben, Dominique Bonnet

Developmental Neurobiology

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Abstract

The biological and clinical behaviors of hematological malignancies can be influenced by the active crosstalk with an altered bone marrow (BM) microenvironment. In the present study, we provide a detailed picture of the BM vasculature in acute myeloid leukemia using intravital two-photon microscopy. We found several abnormalities in the vascular architecture and function in patient-derived xenografts (PDX), such as vascular leakiness and increased hypoxia. Transcriptomic analysis in endothelial cells identified nitric oxide (NO) as major mediator of this phenotype in PDX and in patient-derived biopsies. Moreover, induction chemotherapy failing to restore normal vasculature was associated with a poor prognosis. Inhibition of NO production reduced vascular permeability, preserved normal hematopoietic stem cell function, and improved treatment response in PDX.

Original language	English
Pages (from-to)	324–341
Number of pages	18
Journal	CANCER CELL
Volume	32
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2017.08.001
Publication status	Published - 31 Aug 2017

Keywords

acute myeloid leukemia
hematopoietic stem cells
endothelial cells
vascular permeability
nitric oxide
hypoxia
microenvironment
intravital 2P microscopy
NOS inhibitors
chemotherapy

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Increased Vascular Permeability_PASSARO_Publishedonline31August2017_GOLD VoR (CC BY)Final published version, 6.36 MBLicence: CC BY

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Passaro, D., Di Tullio, A., Abarrategi, A., Rouault-Pierre, K., Foster, K., Ariza-McNaughton, L., Montaner, B., Chakravarty, P., Bhaw, L., Diana, G., Lassailly, F., Gribben, J., & Bonnet, D. (2017). Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia. CANCER CELL, 32(3), 324–341. https://doi.org/10.1016/j.ccell.2017.08.001

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title = "Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia",

abstract = "The biological and clinical behaviors of hematological malignancies can be influenced by the active crosstalk with an altered bone marrow (BM) microenvironment. In the present study, we provide a detailed picture of the BM vasculature in acute myeloid leukemia using intravital two-photon microscopy. We found several abnormalities in the vascular architecture and function in patient-derived xenografts (PDX), such as vascular leakiness and increased hypoxia. Transcriptomic analysis in endothelial cells identified nitric oxide (NO) as major mediator of this phenotype in PDX and in patient-derived biopsies. Moreover, induction chemotherapy failing to restore normal vasculature was associated with a poor prognosis. Inhibition of NO production reduced vascular permeability, preserved normal hematopoietic stem cell function, and improved treatment response in PDX.",

keywords = "acute myeloid leukemia, hematopoietic stem cells, endothelial cells, vascular permeability, nitric oxide, hypoxia, microenvironment, intravital 2P microscopy, NOS inhibitors, chemotherapy",

author = "Diana Passaro and {Di Tullio}, Alessandro and Ander Abarrategi and Kevin Rouault-Pierre and Katie Foster and Linda Ariza-McNaughton and Beatriz Montaner and Probir Chakravarty and Leena Bhaw and Giovanni Diana and Fran{\c c}ois Lassailly and John Gribben and Dominique Bonnet",

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day = "31",

doi = "10.1016/j.ccell.2017.08.001",

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Passaro, D, Di Tullio, A, Abarrategi, A, Rouault-Pierre, K, Foster, K, Ariza-McNaughton, L, Montaner, B, Chakravarty, P, Bhaw, L, Diana, G, Lassailly, F, Gribben, J & Bonnet, D 2017, 'Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia', CANCER CELL, vol. 32, no. 3, pp. 324–341. https://doi.org/10.1016/j.ccell.2017.08.001

TY - JOUR

T1 - Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia

AU - Passaro, Diana

AU - Di Tullio, Alessandro

AU - Abarrategi, Ander

AU - Rouault-Pierre, Kevin

AU - Foster, Katie

AU - Ariza-McNaughton, Linda

AU - Montaner, Beatriz

AU - Chakravarty, Probir

AU - Bhaw, Leena

AU - Diana, Giovanni

AU - Lassailly, François

AU - Gribben, John

AU - Bonnet, Dominique

PY - 2017/8/31

Y1 - 2017/8/31

N2 - The biological and clinical behaviors of hematological malignancies can be influenced by the active crosstalk with an altered bone marrow (BM) microenvironment. In the present study, we provide a detailed picture of the BM vasculature in acute myeloid leukemia using intravital two-photon microscopy. We found several abnormalities in the vascular architecture and function in patient-derived xenografts (PDX), such as vascular leakiness and increased hypoxia. Transcriptomic analysis in endothelial cells identified nitric oxide (NO) as major mediator of this phenotype in PDX and in patient-derived biopsies. Moreover, induction chemotherapy failing to restore normal vasculature was associated with a poor prognosis. Inhibition of NO production reduced vascular permeability, preserved normal hematopoietic stem cell function, and improved treatment response in PDX.

AB - The biological and clinical behaviors of hematological malignancies can be influenced by the active crosstalk with an altered bone marrow (BM) microenvironment. In the present study, we provide a detailed picture of the BM vasculature in acute myeloid leukemia using intravital two-photon microscopy. We found several abnormalities in the vascular architecture and function in patient-derived xenografts (PDX), such as vascular leakiness and increased hypoxia. Transcriptomic analysis in endothelial cells identified nitric oxide (NO) as major mediator of this phenotype in PDX and in patient-derived biopsies. Moreover, induction chemotherapy failing to restore normal vasculature was associated with a poor prognosis. Inhibition of NO production reduced vascular permeability, preserved normal hematopoietic stem cell function, and improved treatment response in PDX.

KW - acute myeloid leukemia

KW - hematopoietic stem cells

KW - endothelial cells

KW - vascular permeability

KW - nitric oxide

KW - hypoxia

KW - microenvironment

KW - intravital 2P microscopy

KW - NOS inhibitors

KW - chemotherapy

U2 - 10.1016/j.ccell.2017.08.001

DO - 10.1016/j.ccell.2017.08.001

M3 - Article

SN - 1535-6108

VL - 32

SP - 324

EP - 341

JO - CANCER CELL

JF - CANCER CELL

IS - 3

ER -

Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia

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Keywords

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