The concept of leukaemic stem cells in acute myeloid leukaemia 25 years on: hitting a moving target.

The concept of leukaemic stem cells (LSCs) was experimentally suggested 25 years ago through seminal data from John Dick's group, who showed that a small fraction of cells from acute myeloid leukaemia (AML) patients were able to be adoptively transferred into immunodeficient mice. The initial estimation of the frequency was 1:250 000 leukaemic cells, clearly indicating the difficulties ahead in translating knowledge on LSCs to the clinical setting. However, the field has steadily grown in interest, expanse and importance, concomitantly with the realisation of the molecular background for AML culminating in the sequencing of hundreds of AML genomes. The literature is now ripe with contributions describing how different molecular aberrations are more or less specific for LSCs, as well as reports showing selectivity in targeting LSCs in comparison to normal haematopoietic stem and progenitor cells. However, we argue here that these important data have not yet been fully realised within the clinical setting. In this clinically focused review, we outline the difficulties in identifying and defining LSCs at the individual patient level, with special emphasis on intraclonal heterogeneity. In addition, we suggest areas of future focus in order to realise the concept as real-time benefit for AML patients.

New insights into RAS in head and neck cancer.

RAS genes are known to be dysregulated in cancer for several decades, and substantial effort has been dedicated to develop agents that reduce RAS expression or block RAS activation. The recent introduction of RAS inhibitors for cancer patients highlights the importance of comprehending RAS alterations in head and neck cancer (HNC). In this regard, we examine the published findings on RAS alterations and pathway activations in HNC, and summarize their role in HNC initiation, progression, and metastasis. Specifically, we focus on the intrinsic role of mutated-RAS on tumor cell signaling and its extrinsic role in determining tumor-microenvironment (TME) heterogeneity, including promoting angiogenesis and enhancing immune escape. Lastly, we summarize the intrinsic and extrinsic role of RAS alterations on therapy resistance to outline the potential of targeting RAS using a single agent or in combination with other therapeutic agents for HNC patients with RAS-activated tumors.