Mechanisms of resistance to apoptosis in human AML blasts: the role of differentiation-induced perturbations of cell-cycle checkpoints

Abstract

Alterations in the response of leukaemic cells to apoptosisinducing stimuli may account for resistance to chemotherapy and treatment failure, either by disruption of the apoptotic pathway itself or by altered DNA repair; quiescent cells and those with disrupted cell-cycle checkpoints may also display decreased apoptosis. Quiescence can be induced by the differentiation of myeloid cells, and this led us to investigate whether the modulation of drug-induced apoptosis associated with differentiation might be a model for quiescence-associated resistance generally. We have demonstrated that resistance to idarubicin-induced apoptosis increased with greater duration of incubation of HL60 and U937 cells with ATRA and 1,25(OH) 2 D3 and that this protective effect correlated with the degree of G0/G1 accumulation. In addition, the cytoprotective effects held for other classes of cytotoxic drugs with different mechanisms of action to idarubicin. Prolonged exposure to idarubicin or vinblastine was associated with diminution of the protective effect and re-entry of cells into cycle. The full cytoprotective effect was restored by resupplementation with ATRA or 1,25(OH) 2 D3 during exposure to idarubicin, with concomitant persistence of G0/G1 accumulation. Differentiating agents prevented the accumulation of leukaemic cells at the G2/M checkpoint in response to low concentrations of idarubicin. Understanding how differentiating agents modulate these cell-cycle checkpoints, and how quiescent cells evade apoptosis, may allow the development of therapeutic strategies to limit such apoptosisinhibiting effects and maximise cell kill from chemotherapy. Leukemia (2000) 14, 620-628.

Bcl-XL is required for heme synthesis during the chemical induction of erythroid differentiation of murine erythroleukemia cells independently of its antiapoptotic function

“…34 Although apoptosis-resistant pathways during differentiation of leukemic cells are poorly understood, there is evidence that members of the Bcl-2 family are involved in the regulation of these processes. For example, Mcl-1 and A1, members of the Bcl-2 family, are required to prevent apoptosis during differentiation of leukemic U937 or NB4 cells.…”

Modulation of cell cycle by graded expression of MLL-AF4 fusion oncoprotein

“…Indeed, in HL60 or U937 cell lines, resistance to drug-induced apoptosis increases with greater duration following incubation with retinoic acid or vitamin D3. 39,40 This protective effect correlates with the degree of G0/ G1 accumulation but is independent of differentiation status or Bcl 2 expression levels.…”

Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia

“…1,2 The Ras/Raf/MEK/ERK pathway is known to control cell proliferation and cell survival, two activities that have a direct impact on tumor promotion and progression. 3,4 We have previously reported that ERK is constitutively activated in more than 50% of primary AMLs but not in normal CD34 þ progenitors 5 and that constitutive ERK activation is an independent prognostic factor for survival in AML (Kornblau et al, Blood 2001; 98: 716a).…”