KLF4 represses MAP2K7 signaling in T-ALL

A major challenge in the therapy of cancer patients is the development of novel drugs that efficiently target cancerinogenic pathways and replace the highly toxic chemodrugs developed over 50 years ago that nonspecifically eliminate highly proliferative cells. The main goal of discovering new cancer specific drugs is not only to improve the treatment response and cure rate but also to prevent the devastating side effects of traditional chemodrugs. This requires refocusing research efforts toward the basic aspects of the pathobiology of cancer and the identification of new molecular targets. The model of the cancer stem cell has gained significant attention recently because this rare cell population is believed to drive chemoresistance and relapses. Despite improvements in risk-adaptive chemotherapy using multiple agents in T cell acute lymphoblastic leukemia (T-ALL), relapse remains the leading cause of cancer-related death in children, with high-risk T-ALL patients in desperate need of an alternative targeted therapy to eliminate leukemiainitiating cells (LIC) [1, 2]. Our group recently reported a novel tumor suppression function for the transcription factor KLF4 in pediatric T-ALL [3, 4], which is best known for reprogramming somatic cells to pluripotent stem cells. We show that KLF4 transcripts are significantly downregulated in samples from children with T-ALL, especially in patients with a poor prognosis, such as the ETP-ALL and TLX groups [3, 5]. Low levels of KLF4 expression correlate with increased CpG methylation (Me) at the proximal promoter (Figure 1), which is confirmed by monitoring the re-expression of KLF4 after treating T-ALL cell lines with a demethylating agent. Although classical tumor suppressors are commonly mutated in cancer patients, to date, only one report describes mutations in the KLF4 gene in T-ALL patients [6]. Nonetheless, the regulation of KLF4 expression by epigenetic mechanisms, such as DNA methylation, is described in several cancers. This is consistent with an emerging paradigm postulating that the epigenome contributes to the inactivation of tumor suppressors and clonal heterogeneity in addition to recurring chromosomal abnormalities and gene mutations. The loss-of-function mouse model of NOTCH1induced T-ALL clearly shows that the genetic deletion of KLF4 leads to a more aggressive disease with a shorter latency and higher penetrance [3]. Strikingly, a hemizygous deletion of the KLF4 gene displays an acceleration of the disease induced by NOTCH1 similar to the homozygous deletion because the heterozygous T-ALL cells display low levels of KLF4 expression that are closer to the homozygous T-ALL cells. A molecular analysis reveals that the rapid development of T-ALL is associated Editorial