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Myelodysplastic Syndromes
Cytokines increase engraftment of
human acute myeloid leukemia cells in immunocompromised mice but not engraftment of human myelodysplastic syndrome cells
Ferrata Storti Foundation
Maria Krevvata,1,* Xiaochuan Shan,1,* Chenghui Zhou,1 Cedric Dos Santos,1 Georges Habineza Ndikuyeze,1 Anthony Secreto,1 Joshua Glover,1
Winifred Trotman,1 Gisela Brake-Silla,1 Selene Nunez-Cruz,2 Gerald Wertheim,3 Hyun-Jeong Ra,1 Elizabeth Griffiths,4 Charalampos Papachristou,5
Gwenn Danet-Desnoyers,1,# and Martin Carroll1,6,#
Haematologica 2018 Volume 103(6):959-971
1Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 2Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 3Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 4Roswell Park Cancer Institute, Buffalo, NY; 5Department of Mathematics, Rowan University, Glassboro,
NJ and 6Veterans Administration Hospital, Philadelphia, PA, USA
ABSTRACT
Patient-derived xenotransplantation models of human myeloid dis- eases including acute myeloid leukemia, myelodysplastic syn- dromes and myeloproliferative neoplasms are essential for studying the biology of the diseases in pre-clinical studies. However, few studies have used these models for comparative purposes. Previous work has shown that acute myeloid leukemia blasts respond to human hematopoi- etic cytokines whereas myelodysplastic syndrome cells do not. We com- pared the engraftment of acute myeloid leukemia cells and myelodys- plastic syndrome cells in NSG mice to that in NSG-S mice, which have transgene expression of human cytokines. We observed that only 50% of all primary acute myeloid leukemia samples (n=77) transplanted in NSG mice provided useful levels of engraftment (>0.5% human blasts in bone marrow). In contrast, 82% of primary acute myeloid leukemia samples engrafted in NSG-S mice with higher leukemic burden and shortened sur- vival. Additionally, all of 5 injected samples from patients with myelodysplastic syndrome showed persistent engraftment on week 6; however, engraftment was mostly low (<2%), did not increase over time, and was only transiently affected by the use of NSG-S mice. Co-injection of mesenchymal stem cells did not enhance human myelodysplastic syn- drome cell engraftment. Overall, we conclude that engraftment of acute myeloid leukemia samples is more robust compared to that of myelodys- plastic syndrome samples and unlike those, acute myeloid leukemia cells respond positively to human cytokines, whereas myelodysplastic syn- drome cells demonstrate a general unresponsiveness to them.
Introduction
Human myeloid neoplasms represent a remarkably diverse array of blood cell diseases. Acute myeloid leukemia (AML) is a clonal hematopoietic disease charac- terized by an abnormal proliferation of immature leukemic blasts and by a hematopoietic differentiation block.1 Myelodysplastic syndromes (MDS) are char- acterized by abnormal cell morphology and ineffective blood cell production. MDS mainly affect the elderly and their pathogenesis is not completely understood but
*MK and XS share co-authorship. #GD-D and MC share senior authorship.
Correspondence:
carroll2@pennmedicine.upenn.edu
Received: October 23, 2017. Accepted: February 22, 2018. Pre-published: March 15, 2018.
doi:10.3324/haematol.2017.183202
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/6/959
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haematologica | 2018; 103(6)
959
ARTICLE