Abnormal morphological and functional nature of bone marrow stromal cells provides preferential support for survival of acute myeloid leukemia cells

Abstract

Hematopoietic progenitors, residing in the bone marrow (BM) niche, are supported by mesenchymal stromal cells (MSCs). Cytogenetic and molecular aberrations in these progenitors lead to acute myeloid leukemia (AML). The BM-MSC role in leukemogenesis is not fully elucidated. In the current study, an ex-vivo system of patient's own stroma (POS), best mimicking the in-vivo BM niche, has been developed aiming to unravel interactions and crosstalk between MSCs and AML cells.POS derived from AML patients at diagnosis (Dx), relapse (Rx) and remission (Rm) was compared to healthy donor MSCs in terms of their morphology, growth pattern, support of leukemia cell viability and cytokine profile. Compared to control MSCs, POS (Dx/Rx, Rm) demonstrated a reduced proliferation rate (35%), significantly slower expansion, enlarged cell area (3-4-fold) and provided preferential support to leukemic cells of the same individual. Cytokine profiling showed significantly higher secreted phosphoprotein-1 (SPP1) expression in Dx/Rx and Rm POS compared to healthy MSCs. Additionally, the angiopoietin-1 expression was elevated in Dx/Rx POS with a further increase in the AML cell presence. In conclusion, the fact that POS derived in active disease and remission exhibited similar morphological and functional characteristics, might imply the involvement of the BM niche in leukemogenesis.

Bone marrow mesenchymal stromal cells from acute myelogenous leukemia patients demonstrate adipogenic differentiation propensity with implications for leukemia cell support

“…The extent to which leukemic blasts reprogram marrow stroma to generate a pro-leukemia environment [28] as compared with intrinsic differences between AML and ND MSCs leading to a preadipogenic phenotype is not certain [50]. Some studies have shown ongoing MSC changes in remission [18] and others have indicated persistence of an altered phenotype through all stages of disease [51].…”

A Novel Immune-Related Competing Endogenous RNA Network Predicts Prognosis of Acute Myeloid Leukemia

“…Molecular inhibitors such as CXCR4 inhibitors, VLA-4 inhibitors and E-selectin inhibitors are currently undergoing clinical trials (6,7). Immune cells and stromal cells are important components of the BM microenvironment, and are also the main influencing factors of leukemia development (8,9). The ESTIMATE program is a common method to explore the microenvironment of many tumors (10).…”

Upregulation ofAKR1C1in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells

“…Studies show increased cytokine and chemokine secretion from MSCs supporting AML cell proliferation and survival (Huang et al , ; Brenner et al , ; Yehudai‐Resheff et al , ). AKR1C1 knockdown altered the secretory cytokine profile of the AML‐MSCs, especially reducing the secretion of MCP‐1, IL‐6, IL‐8 and G‐CSF, which corresponded to reduced mRNA levels of all but IL‐8 .…”

“…The abnormal MSCs in the leukaemic BM microenvironment drive the pathogenesis and progression of leukaemia (Corradi et al , ; Yehudai‐Resheff et al , ) by activating multiple pro‐survival pathways in the blasts (Zeng et al , ). Abdul‐Aziz et al () showed that the pro‐survival effect of AML‐MSCs on the AML blasts was mediated by the MIF/PKCβ/IL8 pathway, while Ruvolo et al () identified LGALS3 as a survival factor in the AML cells.…”