Publication Date:
2012-11-16
Description:
Abstract 1663 The presence of inherently resistant Ph+ leukemic stem cells (LSC) to tyrosine kinase inhibitors (TKI) in chronic phase chronic myelogenous leukemia (CP CML) might be responsible for the long-term disease persistence, requiring the indefinite prolongation of TKI, and represent a reservoir for the initiation of an overt resistance. Despite quiescence, these Ph+ LSC maintain high level interactions with their microenvironment and might display some alterations to different pathways to survive, responsible for disease persistence. In this perspective, we studied some actors involved in the maintenance of the stem cell niche and normal hematopoiesis (Jeanpierre S. et al. Blood 2008), the bone morphogenetic proteins (BMP-2 and BMP-4) in a series of 45 CP CML patients harvested at diagnosis and compared the results to that of 15 normal bone marrow (BM) counterparts from healthy donors. BMPs are members of the TGF-b family, highly secreted by the normal BM stem cell niche, that regulate numerous cellular events such as proliferation, differentiation, migration, adhesion and apoptosis in various cellular systems including hematopiesis. The deregulation of these events is the hallmark of CP CML and they are all involved in the CML disease phenotype in CP. All CML and BM samples were CD34+ purified. RQ-PCRs on total cells, CD34− and CD34+ progenitors for the different members of the BMP pathway show specific alterations in CML: in the CD34+ primitive compartment, BMP-4 itself is downregulated as well as Bambi, Smad1, Smad5, and Runx2 while Smad6 is specifically upregulated. Interestingly, while analyzing the CD34+ and CD34− compartments from individual patients, we observed a differential expression of the signaling pathway inhibitors Smad6 and Follistatin (low levels in leukemic CD34−, high levels in leukemic CD34+ cells when compared to their normal purified counterparts), and BMP-2, BMP-4, and three of the BMP specific receptors (BMP-RIa, BMP-RIb and BMP-RII) are significantly and selectively downregulated in CD34+ CML progenitors. We further characterized the impact of 7-days in vitro exposure to BMP-2 and BMP-4 in 4GF (IL-6, SCF, IL-11, IL-3) serum-free conditions of CD34+ CML and normal BM progenitors using immunophenotypic, CFC and LTC-IC assays. The functional assays results suggest in responding patients, that BMP-4 is able to selectively amplify the genotyped Ph+ LTC-IC compartment (while BMP-2 partly maintains it, whereas TPO amplifies normal Ph− LTC-IC as well as Ph+ LTC-IC) as mentioned in figure 1. Figure 1: Total LTC-IC-derived week 5 colonies per 1000 seeded cells within the responding CML samples. Black bars are CML samples and white bars are normal BM counterparts, (*: p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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