Calpain-mediated X-linked Inhibitor of Apoptosis Degradation in Neutrophil Apoptosis and Its Impairment in Chronic Neutrophilic Leukemia

Abstract

The number of neutrophils in the blood and tissues is controlled by constitutive apoptotic programmed cell death and clearance by phagocytes such as macrophages. Here, we found that calpains cleave the X-linked inhibitor of apoptosis (XIAP) in vitro, producing fragments that are unable to inhibit caspase-3. These fragments were detected in normal neutrophils but were unstable and rapidly degraded. Calpain inhibition delayed tumor necrosis factor-␣-induced apoptosis of normal neutrophils, consistent with a role for calpains in regulating the onset of apoptosis. Interestingly, neutrophils from three patients with chronic neutrophilic leukemia, a rare syndrome characterized by accumulation of mature neutrophils, exhibited decreased -calpain expression, diminished calpain activity, and impaired XIAP degradation. Neutrophils from these patients displayed a delay in spontaneous, Fas-stimulated, and tumor necrosis factor-␣-induced apoptosis. These observations suggest that calpain-mediated XIAP degradation contributes to initiation of apoptosis in normal neutrophils and dysfunction of this regulatory pathway can lead to pathological neutrophil accumulation.

Chronic neutrophilic leukemia 2016: Update on diagnosis, molecular genetics, prognosis, and management

“…In the remaining patients the leukemia was either refractory, the marrow remained hypoplastic following induction chemotherapy or death occurred during attempts at remission induction [5,32,38,41]. A similar situation has been observed among patients with refractory progressive neutrophilia [5,44,46].…”

“…At that time, only 150 cases had been reported in the literature [29,31,32]. A critical review of the literature applying the then recently developed WHO diagnostic criteria, could only confirm this diagnosis in 40 cases, indicating the true rate of occurrence of what is now considered CNL was even lower [5,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47]. In this data set of WHO-defined CNL, the median age at diagnosis was 66 years (range: 15 -86) and 56% were males [5].…”

Functional characterization of mitochondria in neutrophils: a role restricted to apoptosis

“…Probably, this mechanism controls the intrinsic pathway of apoptosis in neutrophils, since the expression of several members of the IAP family has recently been reported in these cells. 24,47,48 Moreover, delay of neutrophil apoptosis due to impaired degradation of XIAP has been associated with the pathological neutrophil accumulation in chronic neutrophilic leukemia, 46,47 underlining the importance of IAP-dependent regulation of neutrophil cell death. At the same time, an intact activation of caspase-9 in cytoplasts, which are devoid of mitochondrial structures (porin), does not exclude that a cytoplasmic factor also might be involved.…”

2-Methoxyestradiol-induced apoptosis in human leukemia cells proceeds through a reactive oxygen species and Akt-dependent process

“…On the other hand, enforced activation of Akt did not block 2ME-induced increases in ROS generation, effectively ruling out the possibility that Akt prevents or attenuates 2ME-mediated oxidative injury. It is of interest that 2ME exposure resulted in downregulation of both Mcl-1 and XIAP, anti-apoptotic proteins that may play a particularly important role in regulating apoptosis in malignant hematopoietic cells (Kobayashi et al, 2002;Bae et al, 2003). The finding that enforced activation of Akt largely blocked 2ME-induced downregulation of XIAP and Mcl-1 may therefore be significant.…”