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Thomas, Egan et al. report that hexokinase 2 localizes to the nucleus of leukaemic and normal haematopoietic cells to maintain stemness by interacting with nuclear proteins and modulating chromatin accessibility independently of its kinase activity.

The role of histone mutations in leukemogenesis remains largely unexplored. In this study of AML, the authors show that histone mutations are early events that drive a more aggressive phenotype.

The mutational mechanisms that produce insertions and deletions that lead to clonal hematopoiesis are poorly understood. Here the authors show evidence that frequent deletions that are relevant to myeloid malignancies could be produced by PARP1-dependent microhomology-mediated end joining.

Analysis of 1,988 cases of B-cell acute lymphoblastic leukemia characterizes 23 subtypes defined by genomic features and shows that two of the subtypes have frequent PAX5 alterations.

Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D, which lead to increased transcriptional activity of the gene, and cellular transformation in vitro.

Molecular heterogeneity of acute myeloid leukaemia (AML) across patients is a major challenge for prognosis and therapy. Here, the authors show that NPM1 mutated AML is a heterogeneous class, consisting of two subtypes which exhibit distinct molecular characteristics, differentiation state, patient survival and drug response.

MHC class I and II molecules generally present endogenous and exogenous peptides, respectively, through distinct mechanisms. Here, the authors show that the class II molecule HLA-DP^84Glyuses both class I and II mechanisms to constitutively present peptides.

The natural product didemnin B inhibits PPT1 and the antiapoptotic protein Mcl-1 in particular types of cancer cells containing a unique genetic profile that correlates with drug sensitivity.

Transcriptomic analysis of BCR-ABL1 lymphoblastic leukemia identifies three subgroups, each associated with a maturation arrest at a specific stage of B-cell progenitor differentiation and distinct genetic and clinical features.

Leukemic stem cells (LSCs) drive chemoresistance and relapse in acute myeloid leukemia. Here, the authors show that the splicing factor RBM17 supports LSCs through avoiding nonsense-mediated decay of pro-leukaemic factors such as the translation initiation factor EIF4A2.

A novel gene expression classifier of AML heterogeneity captures patient-specific variation in leukemia cell composition and predicts clinical responses to treatment.

Ferrando and colleagues analyze matched diagnostic and relapsed acute lymphocytic leukemia by whole-genome sequencing, and perform in vitro genome-wide CRISPR screens, to examine alterations associated with chemotherapy resistance.

With improved breeding and cultivation, ruminant animals can yield food that is better for people and the planet, say Mark C. Eisler, Michael R. F. Lee and colleagues.

The treatment of multiple myeloma is challenging due to high relapse rates. Here the authors show that expression of ADAR1 correlates with poor patient outcomes, and that ADAR1-mediated editing of GLI1 is a mechanism relevant in the context of multiple myeloma progression and drug resistance.

The authors identify pre-leukaemic haematopoietic stem cells (HSCs) in patients with acute myeloid leukaemia; these pre-leukaemic HSCs have the capacity of normal multi-lineage haematopoietic differentiation with a competitive growth advantage over wild-type HSCs, and owing to their persistence may serve as a reservoir for therapeutic resistance and relapse.

Analysing human B-cell acute lymphoblastic leukaemias, this study maps the genetic heterogeneity of cells within a given tumour sample and the evolutionary path by which different subclones have emerged. Leukaemia-initiating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insights into the heterogeneity of these functional subpopulations at the genetic level. This has implications for therapeutic approaches targeting the tumours and specifically leukaemia-initiating cells.

A rapid gene signature test (LSC17) that captures stem cell expression programs in acute myeloid leukaemia patients at diagnosis is associated with therapy response and survival, facilitating initial treatment stratification.

Linda Holmfeldt, Lei Wei et al. report whole-genome and exome sequencing of 40 childhood hypodiploid acute lymphoblastic leukemias.

Several rearrangements of the MLL gene are associated with acute leukemia, including the fusion of MLL with a RAS effector protein, AF6. Here the authors show that the truncated AF6 can induce AF6-MLL dimerization and drive its oncogenic activity.

By functionally isolating stem cells (LSCs) from individuals with leukemia and parsing our their gene expression, Dick and his colleagues find that LSCs have heterogeneous surface markers and frequencies and possess a gene expression profile resembling that of normal hematopoietic stem cells. The gene expression program derived from LSCs could be a general predictor of disease outcome, stratifying risk for cytogenetically normal patients, which suggests that stemness underlies leukemia aggressiveness.

Individuals who are at high risk of developing acute myeloid leukaemia can be identified years before diagnosis using genetic information from blood samples.

Optimal T cell activation requires signaling through the T cell receptor (signal 1), a co-stimulatory receptor (signal 2) and a cytokine receptor (signal 3), yet most chimeric antigen receptors (CARs) lack a domain to transduce signal 3. Kagoya et al. now report their development of a new CAR that incorporates a JAK–STAT cytokine signaling domain and mediates potent antitumor effects.

An immunoprecipitation-based protocol is developed to analyse DNA methylation in small quantities of circulating cell-free DNA, and can detect and classify cancers in plasma samples from several tumour types.

Drugs that induce redifferentiation of cancer cells are efficient only in some subtypes of AML. The authors show that sensitivity to pro-differentiation drugs such as ATRA can be induced by co-treatment with epigenetic drugs. An inhibitor of histone demethylase, LSD1, safely used as an antidepressant in humans, reprograms AML cells and makes them sensitive to the effects of ATRA in vitro and in vivo, suggesting that epigenetic interventions can increase response to cancer treatments.

Identification of the cell types from which relapse arises in acute myeloid leukaemia, by following leukaemia propagation from patient-derived leukaemia samples.

The term myelodysplastic syndromes covers various diseases that are caused by ineffective haematopoiesis in one or more lineages of the bone marrow. How do these diseases arise, and what are the best methods for treating these patients?