Abstract
Alterations in hematopoietic microenvironment of acute lymphoblastic leukemia patients have been claimed to occur, but little is known about the components of marrow stroma in these patients. In this study, we characterized mesenchymal stromal cells (MSCs) isolated from bone marrow (BM) of 45 pediatric patients with acute lymphoblastic leukemia (ALL-MSCs) at diagnosis (day+0) and during chemotherapy treatment (days: +15; +33; +78), the time points being chosen according to the schedule of BM aspirates required by the AIEOP-BFM ALL 2009 treatment protocol. Morphology, proliferative capacity, immunophenotype, differentiation potential, immunomodulatory properties and ability to support long-term hematopoiesis of ALL-MSCs were analysed and compared with those from 41 healthy donors (HD-MSCs). ALL-MSCs were also genetically characterized through array-CGH, conventional karyotyping and FISH analysis. Moreover, we compared ALL-MSCs generated at day+0 with those isolated during chemotherapy. Morphology, immunophenotype, differentiation potential and in vitro life-span did not differ between ALL-MSCs and HD-MSCs. ALL-MSCs showed significantly lower proliferative capacity (p<0.001) and ability to support in vitro hematopoiesis (p = 0.04) as compared with HD-MSCs, while they had similar capacity to inhibit in vitro mitogen-induced T-cell proliferation (p = N.S.). ALL-MSCs showed neither the typical translocations carried by the leukemic clone (when present), nor other genetic abnormalities acquired during ex vivo culture. Our findings indicate that ALL-MSCs display reduced ability to proliferate and to support long-term hematopoiesis in vitro. ALL-MSCs isolated at diagnosis do not differ from those obtained during treatment.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood and arises from clonal proliferation of lymphoid precursors replacing normal hematopoietic cells in the bone marrow (BM) [1,2]
As far as ALL patients are concerned, mesenchymal stromal cells (MSCs) were isolated from 38 patients at diagnosis (d+0), 25 children at day +15, 31 at day +33 and 27 at day +78, the time points being chosen according to the schedule of BM aspirates required by the AIEOP-BFM ALL 2009 treatment protocol
ALL-MSCs have been ex vivo expanded from BM samples collected both at diagnosis and at the different time-points, chosen according to the schedule of BM aspirates of the treatment protocol AIEOP-BFM ALL 2009
Summary
Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood and arises from clonal proliferation of lymphoid precursors replacing normal hematopoietic cells in the bone marrow (BM) [1,2]. Many recurrent genetic and chromosomal alterations, which are known to contribute to the origin of childhood leukemia, have been described in hematopoietic stem cells (HSCs) of ALL patients [2,3,4], a role played by the BM microenvironment, the essential framework where survival, proliferation and differentiation of HSCs take place, cannot be excluded and, it has been proposed by some authors [5,6,7]. MSCs have been successfully employed in patients with chronic inflammatory diseases, such as Crohn’s disease [19,20] In view of their properties and broad potential for clinical application, many efforts are being undertaken to understand the role of MSCs in hematological malignancies [21,22,23,24]
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