Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function.

Chronic myeloid leukemia responds well to therapy targeting the oncogenic fusion protein BCR-ABL1 in chronic phase, but is resistant to treatment after it progresses to blast crisis (BC). BC is characterized by elevated ß-catenin signaling in granulocyte macrophage progenitors (GMPs), which enables this population to function as leukemia stem cells (LSCs) and act as a reservoir for resistance. Because normal hematopoietic stem cells (HSCs) and LSCs depend on ß-catenin signaling for self-renewal, strategies to specifically target BC will require identification of drugable factors capable of distinguishing between self-renewal in BC LSCs and normal HSCs. Here, we show that the MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis is overexpressed in BC GMPs but not normal HSCs, and that MNK kinase-dependent eIF4E phosphorylation at serine 209 activates ß-catenin signaling in BC GMPs. Mechanistically, eIF4E overexpression and phosphorylation leads to increased ß-catenin protein synthesis, whereas MNK-dependent eIF4E phosphorylation is required for nuclear translocation and activation of ß-catenin. Accordingly, we found that a panel of small molecule MNK kinase inhibitors prevented eIF4E phosphorylation, ß-catenin activation, and BC LSC function in vitro and in vivo. Our findings identify the MNK-eIF4E axis as a specific and critical regulator of BC self-renewal, and suggest that pharmacologic inhibition of the MNK kinases may be therapeutically useful in BC chronic myeloid leukemia.

Psychometrics of the Pearlin Mastery Scale among Family Caregivers of Older Adults Who Require Assistance in Activities of Daily Living.

This study examined the psychometric properties of the seven-item mastery scale among 392 family caregivers of care dependent older adults in a tertiary hospital in Singapore. Item response theory (IRT) analysis and confirmatory factor analysis (CFA) were used to assess the scale's psychometric properties. Construct validity was assessed based on correlations between mastery and caregiver burden, depression, and quality of life. Data from the seven-item mastery scale showed acceptable reliability and model fit while IRT analysis showed that response categories were ordered but reflected poor fit for the two positively worded items. Without these two items, responses on the five-item version showed acceptable model fit and had acceptable reliability and high correlation with those on the seven-item version. Item responses on both the seven- and five-item versions show logical correlations with carer self-report on burden, depression, and quality of life. Further psychometric studies of the seven-item mastery scale are warranted. For practical applications such as caregiver screening during hospital admissions, the five-item mastery scale is fit for purpose.