Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy

Abstract

Approximately 20% of B-lineage acute lymphoblastic leukemias are not cured by traditional chemotherapy. The possibility was examined that residual leukemic cells that potentially contribute to relapse are harbored in association with fibroblastic stromal cells in the bone marrow. Modulation of cytarabine (Ara-C) and etoposide (VP-16) efficacy by bone marrow stromal cells in vitro was investigated. Stromal cell coculture was shown to sustain the proliferation of B-lineage leukemic cells and to reduce leukemic cell apoptosis when exposed to Ara-C or VP-16. Direct contact with stromal cells was essential for the protection of leukemic cells during chemotherapy, whereas soluble factors had negligible effect. Specifically, signaling mediated through interaction with the stromal cell adhesion molecule VCAM-1 was required to maintain the maximum viability of leukemic cells during Ara-C and VP-16 exposure. In contrast, the interaction of leukemic cells with fibronectin did not confer significant resistance to either chemotherapeutic agent. These observations suggest a role for the bone marrow microenvironment in modulating the response of B-lineage leukemic cells to Ara-C or VP-16, and they indicate specific molecular interactions that may be important in determining the sensitivity of leukemic cells to treatment.

MLL‐rearranged acute lymphoblastic leukaemia stem cell interactions with bone marrow stroma promote survival and therapeutic resistance that can be overcome with CXCR4 antagonism

“…Maximal growth and survival benefits were observed when there was direct contact between stromal cells and leukaemia cells both in the absence and presence of lestaurtinib. These findings are consistent with a study of B-lineage leukaemia cell lines, which demonstrated that direct contact with stromal cells protected leukaemia cells from cytotoxic chemotherapy, whereas soluble factors had negligible effects (Mudry et al, 2000). We also demonstrated that stromal co-culture promoted the survival of LSCs ex vivo and their ability to propagate leukaemia in vivo.…”

The stromal composition of malignant lymphoid aggregates in bone marrow: variations in architecture and phenotype in different B‐cell tumours

“…Bone marrow stromal cells can influence normal haematopoiesis through the production of soluble cytokines and also through direct contact (Kinashi & Springer, 1994). Similar interactions between bone marrow stromal cells and leukaemic blasts have also been demonstrated (Makrynikola et al, 1991;Mudry et al, 2000). We show here that different types of mature B-cell tumours have different topographic interactions with the pre-existing marrow ARC network and that lymphomatous infiltration can modulate the immunophenotypic profile of these pre-existing stromal cells.…”

“…Following transmigration across the blood vessel wall, tumour cell interactions with ARC become dominant. It has been postulated that ARC provide important cell-to-cell signals for haematopoiesis (Lagneaux et al, 1998;Mudry et al, 2000). The close association of tumour cells to LNGFR + ARC in FL and LPL mimics the tight apposition of ARC to developing megakaryocytic and myeloid forms.…”

Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia

“…Likewise, Khan et al (2007) have shown that exogenous Wnt proteins can increase cell survival and proliferation in the pre-B ALL cell lines Nalm6, Reh and LK63. The bone marrow microenvironment and direct contact between leukaemic cells and marrow stromal cells (MSCs) are essential for leukaemic cell survival and have a protective effect against chemotherapy (Mudry et al, 2000). Yang et al (2013) have demonstrated that the Wnt pathway contributes to the protection of ALL cells by bone marrow stromal support (Yang et al, 2013).…”