Anti‐leukemic effect of PI3K inhibition on chronic myeloid leukemia (CML) cells: shedding new light on the mitigating effect of c‐Myc and autophagy on BKM120 cytotoxicity

The success in the identification of BCR/ABL tyrosine kinase role in the pathogenesis of chronic myeloid leukemia (CML) went as far as to find a path to cure this leukemia; however, compensatory activation of leukomogenic signals get across the message that the small molecule inhibitors of oncogenic pathways, along with tyrosine kinase inhibitors, might be a beneficial approach in CML treatment. The results of the present study showed that the abrogation of the phosphoinositide 3‐kinase (PI3K) pathway using pan‐PI3K inhibitor BKM120 exerted a cytotoxic effect against CML‐derived K562 cells through both the induction of p21‐mediated G2/M arrest and the stimulation of apoptosis. Notably, the apoptotic effect of the inhibitor was further confirmed by the molecular analysis showing that BKM120 significantly increased the expression of pro‐apoptotic genes. To the best of our knowledge, the involvement of autophagy in resistance to BKM120 has not been yet described and our study suggests for the first time that the elevation of autophagy‐related genes might serve as a compensatory pathway to cease the anti‐leukemic effect of BKM120 in K562; since we found a reinforced anti‐survival event when the cells were treated with BKM120 in combination with autophagy inhibitor. In conclusion, the results of the present study showed that the abrogation of PI3K using BKM120 might be a befitting approach in CML treatment, either as a single agent or in a combined‐modal strategy; however, further evaluations including clinical trials and in vivo investigations are demanded to ascertain the safety and the efficacy of the inhibitor in treatment strategies.     

Wogonoside induces depalmitoylation and translocation of PLSCR1 and N‐RAS in primary acute myeloid leukaemia cells

Acute myeloid leukaemia (AML) comprises a range of disparate genetic subtypes, involving complex gene mutations and specific molecular alterations. Post‐translational modifications of specific proteins influence their translocation, stability, aggregation and even leading disease progression. Therapies that target to post‐translational modification of specific proteins in cancer cells represent a novel treatment strategy. Non‐homogenous subcellular distribution of PLSCR1 is involved in the primary AML cell differentiation. However, the nuclear translocation mechanism of PLSCR1 remains poorly understood. Here, we leveraged the observation that nuclear translocation of PLSCR1 could be induced during wogonoside treatment in some primary AML cells, despite their genetic heterogeneity that contributed to the depalmitoylation of PLSCR1 via acyl protein thioesterase 1 (APT‐1), an enzyme catalysing protein depalmitoylation. Besides, we found a similar phenomenon on another AML‐related protein, N‐RAS. Wogonoside inhibited the palmitoylation of small GTPase N‐RAS and enhanced its trafficking into Golgi complex, leading to the inactivation of N‐RAS/RAF1 pathway in some primary AML cells. Taken together, our findings provide new insight into the mechanism of wogonoside‐induced nuclear translocation of PLSCR1 and illuminate the influence of N‐RAS depalmitoylation on its Golgi trafficking and RAF1 signalling inactivation in AML.     

Overexpression of long noncoding RNA HOXA‐AS2 predicts an adverse prognosis and promotes tumorigenesis via SOX4/PI3K/AKT pathway in acute myeloid leukemia

Long noncoding RNAs (lncRNAs) play important roles in diverse cellular processes and carcinogenesis. Homeobox A cluster antisense RNA 2 (HOXA‐AS2) is a 1,048‐basepairs lncRNA located between human HOXA3 and HOXA4 genes, whose overactivation was previously found to promote the proliferation and invasion of solid tumors. However, its clinical and biological roles in acute myeloid leukemia (AML) remain unclear. This study showed that HOXA‐AS2 was overexpressed in AML patients. In addition, the increased HOXA‐AS2 expression was correlated with higher white blood cell and bone marrow blast counts, unfavorable karyotype classification, more measurable residual disease positivity, and earlier death. There was also a tendency toward inferior survival in patients with high HOXA‐AS2 expression, and HOXA‐AS2 was an independent prognostic factor among the normal‐karyotype AMLs. Furthermore, the results of in vitro study showed that silencing HOXA‐AS2 significantly inhibited the growth of leukemic cells by inducing G1/G0‐phase arrest and apoptosis. Further analysis demonstrated that silencing HOXA‐AS2 suppressed the phosphorylation level of PI3K and AKT, which thereafter promoted the expression of P21 and P27. Moreover, it was suggested that the sex‐determining region Y‐box 4 (SOX4), which is closely involved in the PI3K/AKT pathway, might be one of the major downstream targets of HOXA‐AS2. Silencing HOXA‐AS2 decreased the expression of SOX4, whereas the upregulation of SOX4 partially abrogated the inhibitory effect of silencing HOXA‐AS2 on leukemic cells. In conclusion, these findings suggest that HOXA‐AS2 probably functions as an oncogene via SOX4/PI3K/AKT pathway and might be a useful biomarker for the prognostic prediction in AML patients, providing a potential therapeutic target for AML.