Absence or Low Expression of Fas-Associated Protein with Death Domain in Acute Myeloid Leukemia Cells Predicts Resistance to Chemotherapy and Poor Outcome

Abstract

04). In multivariate analysis, FADD؊/low protein expression was independently associated with a poor EFS and overall survival (P ‫؍‬ 0.002 and P ‫؍‬ 0.026, respectively). Importantly, FADD ؊/low protein expression predicted poor EFS even in patients with standard-or good-risk AML (P ‫؍‬ 0.009). Thus, we identified low or absent expression of the FADD protein in leukemic cells at diagnosis as a poor independent prognostic factor that can predict worse clinical outcome even for patients with standard-or good-risk AML.

Modulation of death receptors by cancer therapeutic agents

“…64 Of note, a recent clinical study has shown that absence or low expression of fas-associated with death domain (FADD) in acute myeloid leukemia cells predicts resistance to chemotherapy and poor outcome. 31 These results suggest that the activation of the extrinsic death receptor-mediated apoptotic pathway may play a role in chemotherapy-induced apoptosis.…”

“…It has been shown that low or absent expression of the FADD protein in leukemic cells at diagnosis is a poor independent prognostic factor that can predict worse clinical outcome even for patients with standard-or good-risk AML. 31 However, in lung adenocarcinomas, increased FADD expression is detected in aggressive tumors and is significantly associated with poor survival. 32 It seems that the impact of FADD expression on cancer patient survival is also tumor-type specific.…”

Natural killer cell immune escape in acute myeloid leukemia

“…Release of immunosuppressive cytokines, impaired NK cell-mediated cytotoxicity and IFN-g secretion Altered CD137-CD137L expression 46 Increased NK cell CD137 (CD137L expression is related to monocytic differentiation) Impaired cytotoxicity and IFN-g secretion Release of immunosuppressive cytokines Increased AML cell CD137L High AML cell CD200 expression 47 Reduced frequency of activated NK cells, dull NCR profile Impaired NK cell-mediated cytotoxicity and IFN-g secretion Secretion of soluble immunosuppressive factors For example, TGF-b 51 and IL-2R 48,50,108 Inhibition of NK cell proliferation 109 and cytotoxicity 49,51 Resistance of AML cells to killing Defects in apoptosis mechanisms, [52][53][54] resistance to TRAIL and Fas-mediated killing by high decoy 58,59 or low receptor expression [55][56][57] Impaired NK cell-mediated cytotoxicity activating and inhibitory signals tipping over towards the former. As mentioned before, signaling is relayed through a variety of NK cell activating and inhibitory receptors following ligation (depicted in Figure 2).…”

“…The latter can be achieved by defects in the AML cell apoptosis machinery [52][53][54] and by altered expression or shedding of receptors involved in Fasand TNF-mediated killing, [55][56][57][58][59] two pathways used by NK cells to kill tumor cells. 60 In addition to NK cell abnormalities and AML cell escape mechanisms, the interaction of both cell types with other immune cells provides a third factor contributing towards immune escape ( Table 1).…”

Expression of Recombinant Human FADD, Preparation of Its Polyclonal Antiserum and the Application in Immunoassays

“…A point mutation Phe 25 → Tyr was introduced to suppress the self-aggregation of FADD. Recently increasing evidence showed that absent or low FADD expression was found in different types of tumor cells and was a prognostic factor for poor response to chemotherapy (9,10). The above findings suggest that FADD detection tool of FADD protein is indispensable for the extensive purpose and for further investigating the biological and clinic significance and mechanism of human FADD protein.…”