LETTERS Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras

The cascade comprising Raf, mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) is a therapeutic target in human cancers with deregulated Ras signalling, which includes tumours that have inactivated the Nf1 tumour suppressor 1,2 . Nf1 encodes neurofibromin, a GTPaseactivating protein that terminates Ras signalling by stimulating hydrolysis of Ras-GTP. We compared the effects of inhibitors of MEK in a myeloproliferative disorder (MPD) initiated by inactivating Nf1 in mouse bone marrow and in acute myeloid leukaemias (AMLs) in which cooperating mutations were induced by retroviral insertional mutagenesis. Here we show that MEK inhibitors are ineffective in MPD, but induce objective regression of many Nf1-deficient AMLs. Drug resistance developed because of outgrowth of AML clones that were present before treatment. We cloned clone-specific retroviral integrations to identify candidate resistance genes including Rasgrp1, Rasgrp4 and Mapk14, which encodes p38a. Functional analysis implicated increased RasGRP1 levels and reduced p38 kinase activity in resistance to MEK inhibitors. This approach represents a robust strategy for identifying genes and pathways that modulate how primary cancer cells respond to targeted therapeutics and for probing mechanisms of de novo and acquired resistance. Aberrant Ras signalling contributes to the pathogenesis of myeloid malignancies and can result from acquired RAS mutations or from alternative genetic mechanisms that include FLT3 internal tandem duplications, the BCR-ABL fusion, PTPN11 mutations and NF1 inactivation (reviewed in ref. 3). Children with neurofibromatosis type 1 (NF1) have a 200-to 500-fold excess incidence of juvenile myelomonocytic leukaemia, an aggressive MPD characterized by leukocytosis, splenomegaly and tissue infiltration (reviewed in ref. 4). The bone marrows of affected patients frequently show loss of the normal parental NF1 allele and elevated ERK activity flox/flox pups to identify genes and pathways that might cooperate with Nf1 inactivation to induce progression of MPD to AML 3 . These mice developed acute leukaemia sooner and at a higher rate than control Mx1-Cre-negative littermates that retain normal Nf1 functio

Challenges of Turkish family businesses related to effective management strategies

Interest in family businesses has recently been on the rise in Turkey. The main reason for this is that family firms dominate business life and make a big contribution to job creation and exports. However, running a family business poses intrinsic human dilemmas and unique challenges. Family dynamics tend to affect business dynamics and vice versa. Managing family relationships is an important characteristic of a family business. Managed effectively, a family business offers rewards on many fronts; if managed poorly, the business, including the family, may face many problems, leading to bankruptcy. Therefore, it is important to determine predictors of family business sustainability for the benefit of both the economy and the families owning firms