NGS-defined measurable residual disease (MRD) after initial chemotherapy as a prognostic biomarker for acute myeloid leukemia.

Treated AML patients often have measurable residual disease (MRD) due to persisting low-level clones. This study assessed whether residual post-treatment somatic mutations, detected by NGS, were significantly prognostic for subsequent clinical outcomes. AML patients (n = 128) underwent both pre-and post-treatment testing with the same 42-gene MRD-validated NGS assay.

Analytical validation and performance characteristics of a 48-gene next-generation sequencing panel for detecting potentially actionable genomic alterations in myeloid neoplasms.

Identification of genomic mutations by molecular testing plays an important role in diagnosis, prognosis, and treatment of myeloid neoplasms. Next-generation sequencing (NGS) is an efficient method for simultaneous detection of clinically significant genomic mutations with high sensitivity. Various NGS based in-house developed and commercial myeloid neoplasm panels have been integrated into routine clinical practice.

The rapid Bethesda assay is equivalent to the standard Bethesda assay for detection of factor IX inhibitors in patients with severe haemophilia B.

Introduction: The time-dependent nature of factor VIII (FVIII) inhibitors is well described, and the standard FVIII Bethesda assay used to measure inhibitors incorporates a 2-hour incubation. Despite case reports and reviews describing the immediate-acting nature of factor IX (FIX) inhibitors, many coagulation laboratories continue to use a traditional prolonged incubation for FIX Bethesda assays. To our knowledge, a comprehensive evaluation of the FIX Bethesda assay without incubation has not been reported.

R634W KIT Mutation in an Adult With Systemic Mastocytosis.

Mastocytosis is a clonal neoplasm with the potential to affect various organs within the body. It can range in clinical severity from benign to extremely aggressive. Mastocytosis can be separated into cutaneous, systemic, and leukemic forms, as well as mast-cell sarcoma and extracutaneous mastocytoma.

Gradual Rarefaction of Hematopoietic Precursors and Atrophy in a Depleted microRNA 29a, b and c Environment.

Background: The self-renewing ability of HSCs is fundamental for the maintenance of a pool of bone marrow precursors throughout the life of an individual. The genetic mechanisms underlying such a complex process are still poorly understood.

Results And Significance: Here, we show that constitutive in vivo deletion of miR29ab1 leads to reduced number of HSCs and that miR29ab1 deficient bone marrow cannot repopulate the bone marrow of irradiated mice.

Jumping translocations, a novel finding in chronic lymphocytic leukaemia.

A jumping translocation (JT) is a rare cytogenetic aberration that can occur in haematological malignancy. It involves the translocation of the same fragment of donor chromosome onto two or more recipient chromosomes, typically in different cells. In this study, we describe the first series of chronic lymphocytic leukaemia (CLL) patients with JTs reported to date.

A novel role of CYP2E1 in human megakaryocyte development.

Cytochrome P450 2E1 (CYP2E1) has active roles in bioconversion and biotransformation in humans. Although predominantly present in hepatocytes, CYP2E1 has also been found in hematopoietic stem cells and subtypes of acute myeloid leukemia with unknown clinical significance except for the metabolism of anti-fungal drugs. In the present study, we demonstrated a novel role of CYP2E1 inducing megakaryocyte development in human hematopoietic stem cells and leukemia bipotent K562 cells.

Submicroscopic deletion of 5q involving tumor suppressor genes (CTNNA1, HSPA9) and copy neutral loss of heterozygosity associated with TET2 and EZH2 mutations in a case of MDS with normal chromosome and FISH results.

Advances in genome-wide molecular cytogenetics allow identification of novel submicroscopic DNA copy number alterations (aCNAs) and copy-neutral loss of heterozygosity (cnLOH) resulting in homozygosity for known gene mutations in myeloid neoplasms. We describe the use of an oligo-SNP array for genomic profiling of aCNA and cnLOH, together with sequence analysis of recurrently mutated genes, in a patient with myelodysplastic syndrome (MDS) presenting with normal karyotype and FISH results. Oligo-SNP array analysis revealed a hemizygous deletion of 896 kb at chromosome 5q31.

Inter-reader variability in follicular lymphoma grading: Conventional and digital reading.

Context: Pathologists grade follicular lymphoma (FL) cases by selecting 10, random high power fields (HPFs), counting the number of centroblasts (CBs) in these HPFs under the microscope and then calculating the average CB count for the whole slide. Previous studies have demonstrated that there is high inter-reader variability among pathologists using this methodology in grading.

Aims: The objective of this study was to explore if newly available digital reading technologies can reduce inter-reader variability.

Unique in vitro and in vivo thrombopoietic activities of ingenol 3,20 dibenzoate, a Ca(++)-independent protein kinase C isoform agonist.

Thrombopoiesis following severe bone marrow injury frequently is delayed, thereby resulting in life-threatening thrombocytopenia for which there are limited treatment options. The reasons for these delays in recovery are not well understood. Protein kinase C (PKC) agonists promote megakaryocyte differentiation in leukemia cell lines and primary cells.

Therapy-related pro-B cell acute lymphoblastic leukemia: report of two patients with MLL amplification.

Improvements in chemotherapy and medical support of patients treated with chemotherapy and radiation have led to an ever-increasing number of cancer survivors. Unfortunately, a small fraction of these patients develop secondary hematologic malignancies as a consequence of their exposure to genotoxic anti-cancer regimens. Most of these are myeloid malignancies, therapy-related acute myeloid leukemia (t-AML) or myelodysplasia (t-MDS); however, a small but growing body of literature exists, which describes therapy-related acute lymphoblastic leukemias (t-ALL).

Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation.

How inflammation causes cancer is unclear. Interleukin-15 (IL-15) is a pro-inflammatory cytokine elevated in human large granular lymphocyte (LGL) leukemia. Mice overexpressing IL-15 develop LGL leukemia.

Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model.

Constitutive activation of FMS-like tyrosine kinase 3 (FLT3) by internal tandem duplication (ITD) mutations is one of the most common molecular alterations known in acute myeloid leukemia (AML). To investigate the role FLT3/ITD mutations play in the development of leukemia, we generated a FLT3/ITD knock-in mouse model by inserting an ITD mutation into the juxtamembrane domain of murine Flt3. FLT3wt/ITD mice developed myeloproliferative disease, characterized by splenomegaly, leukocytosis, and myeloid hypercellularity, which progressed to mortality by 6 to 20 months.

Telomere length shortening in Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a clonal, proliferative disorder of phenotypically immature CD1a(+) Langerhans cells (LC). The aetiology of LCH is unknown and data supporting an immune dysregulatory disorder as well as a clonal neoplasm have been reported. Telomere shortening has been associated with cancers and premalignant lesions as well as promoting chromosomal instability.

FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications.

The prognostic relevance of FLT3 D835/I836 mutations (FLT3-TKD) in cytogenetically normal acute myeloid leukemia (CN-AML) remains to be established. After excluding patients with FLT3 internal tandem duplications, we compared treatment outcome of 16 de novo CN-AML patients with FLT3-TKD with that of 123 patients with wild-type FLT3 (FLT3-WT), less than 60 years of age and similarly treated on Cancer and Leukemia Group B protocols. All FLT3-TKD(+) patients and 85% of FLT3-WT patients achieved a complete remission (P = .

Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease.

Evidence is continuing to accumulate that the FMS-like tyrosine kinase 3 (FLT3) receptor plays an important role in acute leukemias. Acute myeloid leukemia patients often express constitutive active mutant forms of the receptor in their leukemic cells. A t(12;13)(p13;q12) translocation between Tel and the FLT3 receptor was recently described in a patient with myeloproliferative disease (MPD).

Activation of transferrin receptor 1 by c-Myc enhances cellular proliferation and tumorigenesis.

Overexpression of transferrin receptor 1 (TFRC1), a major mediator of iron uptake in mammalian cells, is a common feature of human malignancies. Therapeutic strategies designed to interfere with tumor iron metabolism have targeted TFRC1. The c-Myc oncogenic transcription factor stimulates proliferation and growth by activating thousands of target genes.

Central nervous system lymphoma associated with mycophenolate mofetil in lupus nephritis.

Lymphomas, both within and outside the central nervous system, are uncommon among patients with systemic lupus erythematosus (SLE). We describe a 58-year old Korean woman with SLE who presented with acute headache and confusion in the setting of prednisone and mycophenolate mofetil (MMF) therapy used to treat focal proliferative and membranous lupus nephritis. Three-dimensional brain magnetic resonance imaging (MRI) showed two peripherally ('ring') enhancing lesions within the basal ganglia, bilaterally, with associated mass effect and subfalcine herniation.

Jun blockade of erythropoiesis: role for repression of GATA-1 by HERP2.

Although Jun upregulation and activation have been established as critical to oncogenesis, the relevant downstream pathways remain incompletely characterized. In this study, we found that c-Jun blocks erythroid differentiation in primary human hematopoietic progenitors and, correspondingly, that Jun factors block transcriptional activation by GATA-1, the central regulator of erythroid differentiation. Mutagenesis of c-Jun suggested that its repression of GATA-1 occurs through a transcriptional mechanism involving activation of downstream genes.

Defective human MutY phosphorylation exists in colorectal cancer cell lines with wild-type MutY alleles.

Oxidative DNA damage can generate a variety of cytotoxic DNA lesions such as 8-oxoguanine (8-oxoG), which is one of the most mutagenic bases formed from oxidation of genomic DNA because 8-oxoG can readily mispair with either cytosine or adenine. If unrepaired, further replication of A.8-oxoG mispairs results in C:G to A:T transversions, a form of genomic instability.

RUNX1 and GATA-1 coexpression and cooperation in megakaryocytic differentiation.

Megakaryocytic and erythroid lineages derive from a common bipotential progenitor and share many transcription factors, most prominently factors of the GATA zinc-finger family. Little is known about transcription factors unique to the megakaryocytic lineage that might program divergence from the erythroid pathway. To identify such factors, we used the K562 system in which megakaryocyte lineage commitment is dependent on sustained extracellular regulatory kinase (ERK) activation and is inhibited by stromal cell contact.