Prognostic value of the expression of phosphatase and tensin homolog and CD44 in elderly patients with refractory acute myeloid leukemia

Abstract

The leukemic stem cell marker CD44, has been reported to have prognostic significance in hematological malignancies. The present study therefore aimed to evaluate whether the expression levels of CD44 and the associated pathway components are associated with the survival rate of elderly patients with refractory acute myeloid leukemia (AML). A total of 20 elderly patients diagnosed with refractory AML were divided into two groups, following induction chemotherapy: Complete remission (CR, n=9) and non-remission (NR. n=11). Bone marrow biopsy specimens were collected, expression levels of CD44, phosphatase and tensin homolog (PTEN), mammalian target of rapamycin (mTOR) and nuclear factor-κB (NF-κB) were analyzed by immunohistochemistry and the captured images were analyzed in a blinded manner using Image Pro Plus software, version 6.0. The overall survival rates (OS) of the patients were then analyzed with log rank, and the correlation between CD44, PTEN, mTOR and NF-κB expression levels and patients survival rates were statistically analyzed using Pearson's method. Significant differences were observed between the CR and NR groups for PTEN (P=0.025) and CD44 (P=0.020) expression levels. Positive CD44 expression was significantly correlated with poor overall survival, with a hazard ratio of 6.281 (95% CI, 1.78-22.12; P=0.0042). The mean OS was 4.00 months for patients that demonstrated positive CD44 expression, compared with 9.27 months for patients that demonstrated negative CD44 expression. A tendency towards reduced survival rates was also observed in patients negative for PTEN expression, when compared with that of PTEN-positive patients. The mean OS was 4.81 months in PTEN-negative patients vs. 8.8 months in PTEN-positive patients, with a hazard ratio of 2.689 (95%CI, 0.89-8.08; P=0.078). Patients that exhibited PTEN-positive and CD44-negative expression, survived significantly longer than patients that demonstrated PTEN-negative and CD44-positive expression (mean OS, 9.86 vs 2.67 months; hazard ratio=0.037; 95% CI, 0.006-0.222, P=0.0006). The expression levels of NF-κB and mTOR were slightly increased in the NR group compared with those of the CR group, although no significant differences were identified. PTEN and CD44 expression levels demonstrated trends towards negative correlation. In conclusion, the expression levels of CD44 and PTEN may be useful markers to predict the prognosis of elderly patients with refractory AML.

Considerations and challenges for patients with refractory and relapsed acute myeloid leukaemia

“…Mutations of other genes, including CEBPA, WT1, IDH1, and IDH2, have not been shown to significantly affect prognosis in rrAML [40], although data are limited. Recently, a small study (n = 20) found that expression levels of CD44 and of phosphatase and tensin homolog (PTEN) may have prognostic value in elderly patients with refractory AML; specifically, positive CD44 expression was significantly correlated with poor OS (hazard ratio [HR]: 6.281 [95% CI, 1.78-22.12; P = 0.0042]), negative PTEN expression was associated with a tendency toward reduced survival (HR: 2.689 [95% CI, 0.89-8.08; P = 0.078]), and patients who were both CD44 negative and PTEN positive had significantly increased survival compared with those who were CD44 positive and PTEN negative (HR: 0.037 [95% CI, 0.006-0.222; P = 0.0006]) [47]. Molecular abnormalities may ultimately play a role in treatment selection; a number of targeted therapies are currently in development [48].…”

Leukemia stem cell immunophenotyping tool for diagnostic, prognosis, and therapeutics

“…These cells are often referred to as leukemia-initiating cells (LICs; Huang, Li, Li, Zhao, & Chen, 2015;Terwijn et al, 2014), as they reliably reproduce the donorʼs disease in xenograft models (De Grandis et al, 2017;Picot et al, 2017;van Gosliga et al, 2007); however, engraftment potential assays are needed to justify such denomination (De Grandis et al, 2017;Garg, Shanmukhaiah et al, 2016), and these cells are widely used in experimental cancer research but less frequently in diagnosis and in the clinic.…”

“…Their quiescent status is a key point as well, since it protects against drugs that target actively cycling cells, making them resistant to most available tyrosine kinase inhibitors (Deshpande et al, 2006;Thielen et al, 2016). Additionally, apoptosis entrance protection (de Figueiredo-Pontes et al, 2008) and aging avoidance (Kronenwett et al, 2005) have been described among other mechanisms to explain cell persistence and relapse occurrence (Bertrand et al, 2012;Blume et al, 2018;de Figueiredo-Pontes et al, 2008;Huang et al, 2015;Lainey et al, 2012;Picot et al, 2017;Qiu et al, 2014).…”

“…Both CD123 and CD25, aside from CD96, appear to be equally and highly predictive of a poor prognosis (Bonardi et al, ; Yabushita et al, ). CD96, also known as T‐cell Ig mucin 3 or Tactile (Garg, Shanmukhaiah et al, ; Hosen et al, ; Qiu et al, ; Yabushita et al, ; Zeijlemaker et al, ), in contrast to CD123 and CD25, does not participate in cytokine signaling and is related to homing properties (Garg, Ghosh et al, ; Garg, Shanmukhaiah et al, ; Hosen et al, ), similar to CD44, which was described as possible surface marker of LSCs (Beghini et al, ; De Grandis et al, ; Garg, Ghosh et al, ; Garg, Shanmukhaiah et al, ; Huang et al, ; Qiu et al, ; Valent et al, ; Yabushita et al, ; Zeijlemaker et al, ).…”

Recent advances in hyaluronic acid-decorated nanocarriers for targeted cancer therapy

“…Together with CD44s, insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) has been investigated as a biomarker for predicting the risk of hepatocellular carcinoma at initial diagnosis in cases of recurrence [38]. In another study, the correlation between expression levels of PTEN and CD44 was revealed, in which the survival of patients who were PTEN positive but CD44 negative was higher than in patients who were PTEN negative but CD44 positive [39]. …”