B- and T-cell acute lymphoblastic leukemias evade chemotherapy at distinct sites in the bone marrow

Persistence of residual disease after induction chemotherapy is a strong predictor of relapse in acute lymphoblastic leukemia (ALL). The bone marrow microenvironment may support escape from treatment. Using three-dimensional fluorescence imaging of ten primary ALL xenografts we identified sites of p...

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Published in	Haematologica (Roma) Vol. 108; no. 5; pp. 1244 - 1258
Main Authors	Barz, Malwine J., Behrmann, Lena, Capron, Danaëlle, Zuchtriegel, Gabriele, Steffen, Fabio D., Kunz, Leo, Zhang, Yang, Vermeerbergen, Iria Jimenez, Marovca, Blerim, Kirschmann, Moritz, Zech, Antonia, Nombela-Arrieta, César, Ziegler, Urs, Schroeder, Timm, Bornhauser, Beat, Bourquin, Jean-Pierre
Format	Journal Article
Language	English
Published	Italy Fondazione Ferrata Storti 01.05.2023 Ferrata Storti Foundation
Subjects	Antineoplastic Combined Chemotherapy Protocols - therapeutic use ARTICLE - Acute Lymphoblastic Leukemia Bone Marrow Burkitt Lymphoma - drug therapy Humans Leukemia, Biphenotypic, Acute Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Tumor Microenvironment
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ISSN	0390-6078 1592-8721 1592-8721
DOI	10.3324/haematol.2021.280451

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Summary:	Persistence of residual disease after induction chemotherapy is a strong predictor of relapse in acute lymphoblastic leukemia (ALL). The bone marrow microenvironment may support escape from treatment. Using three-dimensional fluorescence imaging of ten primary ALL xenografts we identified sites of predilection in the bone marrow for resistance to induction with dexamethasone, vincristine and doxorubicin. We detected B-cell precursor ALL cells predominantly in the perisinusoidal space at early engraftment and after chemotherapy. The spatial distribution of T-ALL cells was more widespread with contacts to endosteum, nestin+ pericytes and sinusoids. Dispersion of T-ALL cells in the bone marrow increased under chemotherapeutic pressure. A subset of slowly dividing ALL cells was transiently detected upon shortterm chemotherapy, but not at residual disease after chemotherapy, challenging the notion that ALL cells escape treatment by direct induction of a dormant state in the niche. These lineage-dependent differences point to niche interactions that may be more specifically exploitable to improve treatment.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Disclosures Contributions The data supporting the findings of this study are available upon request to the author for correspondence. MJB, LB, DC, GZ and IJV designed and carried out experiments. MJB, LB, DC, GZ and FDS analyzed data. MJB, LB, DC, GZ, IJV and BM performed and supported the xenograft experiments. DC and GZ performed most of the xenograft experiments and collected the imaging data. LB established the 3D imaging protocols. AZ, CN-A and UZ provided technical support and data interpretation for the 3D microscopy. MK wrote the Matlab scripts. MK, LK, YZ and TS contributed to image processing and analysis. BB and J-PB supervised the study; MJB, LB, DC, GZ, FDS, BB and J-PB wrote the manuscript. All authors approved the final version of the manuscript. No conflicts of interest to disclose. Data-sharing statement
ISSN:	0390-6078 1592-8721 1592-8721
DOI:	10.3324/haematol.2021.280451