Inherited cancer predisposing mutations in patients with therapy-related myeloid neoplasms.

Some patients with therapy-related myeloid neoplasms (t-MN) may have unsuspected inherited cancer predisposition syndrome (CPS). We propose a set of clinical criteria to identify t-MN patients with high risk of CPS (HR-CPS). Among 225 t-MN patients with an antecedent non-myeloid malignancy, our clinical criteria identified 52 (23%) HR-CPS patients.

EGR1 Haploinsufficiency Confers a Fitness Advantage to Hematopoietic Stem Cells Following Chemotherapy.

Therapy-related myeloid neoplasms (t-MNs) share many clinical and molecular characteristics with AML de novo in the elderly. One common factor is that they arise in the setting of chronic inflammation, likely because of advanced age or chemotherapy-induced senescence. Here, we examined the effect of haploinsufficient loss of the del(5q) tumor suppressor gene, EGR1, commonly deleted in high-risk MNs.

International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data.

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification.

Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in T Acute Lymphoblastic Leukemia.

T lymphocyte acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease affecting T cells at multiple stages of their development and is characterized by frequent genomic alterations. The transcription factor LEF1 is inactivated through mutation in a subset of T-ALL cases but elevated LEF1 expression and activating mutations have also been identified in this disease. Here we show, in a murine model of T-ALL arising due to inactivation, that the developmental timing of mutation impacts its ability to function as a cooperative tumor suppressor or oncogene.

HUGO Gene Nomenclature Committee (HGNC) recommendations for the designation of gene fusions.

Gene fusions have been discussed in the scientific literature since they were first detected in cancer cells in the early 1980s. There is currently no standardized way to denote the genes involved in fusions, but in the majority of publications the gene symbols in question are listed either separated by a hyphen (-) or by a forward slash (/). Both types of designation suffer from important shortcomings.

Therapy-related myeloid neoplasms in 109 patients after radiation monotherapy.

Therapy-related myeloid neoplasms (t-MNs) are a late complication of cytotoxic therapy and are defined as a distinct entity by the World Health Organization. Although the link between chemotherapy exposure and risk of subsequent t-MN is well described, the association between radiation monotherapy (RT) and t-MN risk is less definitive. We analyzed 109 consecutive patients who developed t-MNs after RT and describe latencies, cytogenetic profile, mutation analyses, and clinical outcomes.

Cohort profile: the ChicagO Multiethnic Prevention and Surveillance Study (COMPASS).

Purpose: The ChicagO Multiethnic Prevention and Surveillance Study or 'COMPASS' is a population-based cohort study with a goal to examine the risk and determinants of cancer and chronic disease. COMPASS aims to address factors causing and/or exacerbating health disparities using a precision health approach by recruiting diverse participants in Chicago, with an emphasis on those historically underrepresented in biomedical research.

Participants: Nearly 8000 participants have been recruited from 72 of the 77 Chicago community areas.

Cytotoxic Therapy-Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms.

Therapy-related myeloid neoplasms (t-MNs) following treatment with alkylating agents are characterized by a del(5q), complex karyotypes, alterations of and a dismal prognosis. To decipher the molecular pathway(s) leading to the pathogenesis of del(5q) t-MN and the effect(s) of cytotoxic therapy on the marrow microenvironment, we developed a mouse model with loss of two key del(5q) genes, and , in hematopoietic cells. We used the well-characterized drug, N-ethyl-N-nitrosurea (ENU) to demonstrate that alkylating agent exposure of stromal cells in the microenvironment increases the incidence of myeloid disease.

A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia.

In this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) and mitoxantrone (mito) based on the hypothesis that epigenetic priming with a hypomethylating agent before cytotoxic chemotherapy would improve response rates in patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory disease. The primary objective was to establish the recommended phase 2 dose of AZA given before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) received AZA at 37.

The Harmful Consequences of Increased Fitness in Hematopoietic Stem Cells.

Clonal hematopoiesis of indeterminate potential (CHIP) describes clonal selection of a hematopoietic stem cell with a somatic mutation that confers increased fitness, influenced by a selective environment such as aging, inflammation, or therapeutic exposure. In this issue of Cell Stem Cell, Hsu et al. (2018) explore the role of cytotoxic therapy in disease-relevant CHIP.

Clonal architecture in patients with myelodysplastic syndromes and double or minor complex abnormalities: Detailed analysis of clonal composition, involved abnormalities, and prognostic significance.

The study analyzes the clonal architecture and the abnormalities involved in a series of 191 patients with myelodysplastic syndromes (MDS) and 2-3 clonal abnormalities. All patients were extracted from an international database. The patients were classified into six clonal subtypes (2A-3C) based on the number of abnormalities and the presentation of unrelated clones (UC) and/or a clonal evolution.

Differing clinical features between Japanese and Caucasian patients with myelodysplastic syndromes: Analysis from the International Working Group for Prognosis of MDS.

Clinical features of myelodysplastic syndromes (MDS) could be influenced by many factors, such as disease intrinsic factors (e.g., morphologic, cytogenetic, molecular), extrinsic factors (e.

Regulated Capture of Vκ Gene Topologically Associating Domains by Transcription Factories.

Expression of vast repertoires of antigen receptors by lymphocytes, with each cell expressing a single receptor, requires stochastic activation of individual variable (V) genes for transcription and recombination. How this occurs remains unknown. Using single-cell RNA sequencing (scRNA-seq) and allelic variation, we show that individual pre-B cells monoallelically transcribe divergent arrays of Vκ genes, thereby opening stochastic repertoires for subsequent Vκ-Jκ recombination.

Author Correction: RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia.

In the originally published version of this Article, the GAPDH loading control blot in Fig. 1a was inadvertently replaced with a duplicate of the DNMT2 blot in the same panel during assembly of the figure. This has now been corrected in both the PDF and HTML versions of the Article.

Publisher Correction: miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia.

This corrects the article DOI: 10.1038/ncomms1681.

RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia.

The roles of RNA 5-methylcytosine (RNA:mC) and RNA:mC methyltransferases (RCMTs) in lineage-associated chromatin organization and drug response/resistance are unclear. Here we demonstrate that the RCMTs, namely NSUN3 and DNMT2, directly bind hnRNPK, a conserved RNA-binding protein. hnRNPK interacts with the lineage-determining transcription factors (TFs), GATA1 and SPI1/PU.

Therapy-related myeloid neoplasms: when genetics and environment collide.

Therapy-related myeloid neoplasms (t-MN) arise as a late effect of chemotherapy and/or radiation administered for a primary condition, typically a malignant disease, solid organ transplant or autoimmune disease. Survival is measured in months, not years, making t-MN one of the most aggressive and lethal cancers. In this Review, we discuss recent developments that reframe our understanding of the genetic and environmental aetiology of t-MN.

Inhibition of WNT signaling in the bone marrow niche prevents the development of MDS in the MDS mouse model.

There is accumulating evidence that functional alteration(s) of the bone marrow (BM) microenvironment contribute to the development of some myeloid disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition to a cell-intrinsic role of WNT activation in leukemia stem cells, WNT activation in the BM niche is also thought to contribute to the pathogenesis of MDS and AML. We previously showed that the -haploinsufficient mice ( ) model MDS induced by an aberrant BM microenvironment.

KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer.

Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in Kras "knockin" mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse.

Diagnostic evaluation of RNA sequencing for the detection of genetic abnormalities associated with Ph-like acute lymphoblastic leukemia (ALL).

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a molecular subtype of high-risk B-cell ALL characterized by formation of abnormal gene fusions involving tyrosine kinase (TK) and cytokine receptor genes and activation of TK signaling. Because of the diversity of associated genetic changes, the detection of Ph-like ALL cases currently requires multiple cytogenetic and molecular assays; thus, our goal was to develop a consolidated workflow for detecting genetic abnormalities in Ph-like ALL. We found that total and targeted RNA sequencing (RNAseq)-based approach allowed the detection of abnormal fusion transcripts (EBF1-PDGFRB, P2RY8-CRLF2, RCSD1-ABL1, and RCSD1-ABL2).