Novel somatic mutations in UBA1 as a cause of VEXAS syndrome.

Poulter and colleagues describe a series from the United Kingdom of 10 male patients with VEXAS syndrome, including 2 with novel genetic changes affecting methionine 41 of E1.

Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts.

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic.

Telomere length is an independent prognostic marker in MDS but not in de novo AML.

Telomere dysfunction is implicated in the generation of large-scale genomic rearrangements that drive progression to malignancy. In this study we used high-resolution single telomere length analysis (STELA) to examine the potential role of telomere dysfunction in 80 myelodysplastic syndrome (MDS) and 95 de novo acute myeloid leukaemia (AML) patients. Despite the MDS cohort being older, they had significantly longer telomeres than the AML cohort (P < 0·0001) where telomere length was also significantly shorter in younger AML patients (age <60 years) (P = 0·02) and in FLT3 internal tandem duplication-mutated AML patients (P = 0·03).

Impact of socioeconomic status on disease phenotype, genomic landscape and outcomes in myelodysplastic syndromes.

Genetic and epigenetic alterations contribute to the biological and clinical characteristics of myelodysplastic syndromes (MDS), but a role for socioeconomic environment remains unclear. Here, socioeconomic status (SES) for 283 MDS patients was estimated using the Scottish Index of Multiple Deprivation tool. Indices were assigned to quintile categorical indicators ranked from SES1 (lowest) to SES5 (highest).

Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression.

The diagnosis of myelodysplastic syndromes (MDS) remains problematic due to the subjective nature of morphologic assessment. The reported high frequency of somatic mutations and increased structural variants by array-based cytogenetics have provided potential objective markers of disease; however, this has been complicated by reports of similar abnormalities in the healthy population. We aimed to identify distinguishing features between those with early MDS and reported healthy individuals by characterizing 69 patients who, following a nondiagnostic marrow, developed progressive dysplasia or acute myeloid leukemia.

An intensive approach to treatment for older patients with relapsed isolated NPM1 mutated AML.

We present a short case series of elderly patients with NK-AML and isolated NPM1 mutation who were treated with intensive chemotherapy, achieving significant CRs multiple times on reinduction, even with a single course.We hope to highlight the NPM1 as a molecular marker in elderly for consideration of aggressive treatment, even if abridged, as this subset may achieve a durable, good quality responses at diagnosis or subsequent relapses.

Occupational and environmental etiology of MDS.

The myelodysplastic syndromes (MDS) are morphologically and genetically heterogeneous, and as such a single etiological factor is implausible. Therapy-related MDS has a clear etiology but the predisposition factors remain unclear. Most MDS (>90%) is not therapy-related and an etiology for this majority of patients, and indeed of better defined (morphological or genetic) subgroups cannot yet be ascertained.

Durable second complete remissions with oral melphalan in hypocellular Acute Myeloid Leukemia and Refractory Anemia with Excess Blast with normal karyotype relapsing after intensive chemotherapy.

We treated six patients who had relapsed after intensive chemotherapy, presenting initially with AML or RAEB, a hypocellular marrow and normal karyotype, and who were deemed unsuitable for re-induction with intensive chemotherapy, with low dose oral melphalan. Three of six patients achieved complete hematological response with no significant toxicity and with a duration of 12, 8 and 3+ months respectively. These three patients had received only two prior courses of chemotherapy each, in contrast to non-responders who were more heavily pre-treated.

Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192.

Histone deacetylase inhibitors (HDACIs) are in advanced clinical development as cancer therapeutic agents. However, first generation HDACIs such as butyrate and valproate are simple short chain aliphatic compounds with moieties resembling acetyl groups, and have a broad spectrum of activity against HDACs. More complex second generation HDACIs undergoing clinical trials, such as the benzamide group compounds MS-275 and MGCD0103, are specific primarily for HDAC1 and HDAC2.

Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms.

In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS.

Epigenetic mechanisms regulating normal and malignant haematopoiesis: new therapeutic targets for clinical medicine.

It is now well established that epigenetic phenomena and aberrant gene regulation play a major role in carcinogenesis. These include aberrant gene silencing by imposing inactive histone marks on promoters, aberrant methylation of DNA at CpG islands, and the active repression of promoters by oncoproteins. In addition, many malignant cells also show aberrant gene activation due to constitutively active signalling.

Microarray-based classifiers and prognosis models identify subgroups with distinct clinical outcomes and high risk of AML transformation of myelodysplastic syndrome.

The diagnosis of myelodysplastic syndrome (MDS) currently relies primarily on the morphologic assessment of the patient's bone marrow and peripheral blood cells. Moreover, prognostic scoring systems rely on observer-dependent assessments of blast percentage and dysplasia. Gene expression profiling could enhance current diagnostic and prognostic systems by providing a set of standardized, objective gene signatures.

Analysis of the CD33-related siglec family reveals that Siglec-9 is an endocytic receptor expressed on subsets of acute myeloid leukemia cells and absent from normal hematopoietic progenitors.

CD33 (Siglec-3) is expressed on most acute myeloid leukemia (AML) cells and is currently being exploited as a therapeutic target. The purpose of this study was to investigate the expression pattern and potential utility of the seven recently described CD33-related siglecs as markers in AML. Besides CD33, Siglec-9 was the most highly expressed, particularly on AML cells with features of monocytic differentiation that also expressed Siglecs-5 and -7.

Etiology of acute myeloid leukemia in the elderly.

The biologic and epidemiologic study of acute myeloid leukaemia (AML) in the elderly is in its infancy. Most epidemiologic data attempting to ascertain the etiology of AML have been obtained from younger cohorts or patients with therapy-related AML. The increasing prevalence of deletional and complex karyotypes in elderly AML patients implies a cumulative genotoxicity over time for this subgroup, given the similar spectrum of abnormalities following exposure to known genotoxic agents such as alkylating chemotherapeutic drugs.

Chronic myelomonocytic leukemia: lost in classification?

Chronic myelomonocytic leukemia (CMML) comprises a spectrum of disease variably considered as a myelodysplastic (MDS) and/or myeloproliferative (MPD) disorder. Now classified by the WHO within a separate nosological group from MDS or MPD, the reality is that there is a dynamic of evolution through increasing monocyte counts in one-third of patients. The principal clinical difference between CMML and other MPD is the presence of ineffective hematopoiesis, manifesting as more frequent anemia and thrombocytopenia in CMML.

Treatment strategies and issues in low/intermediate-1-risk myelodysplastic syndrome (MDS) patients.

Myelodysplastic syndromes (MDS) are a heterogeneous group of progressive bone marrow neoplastic disorders associated with increased risk for transformation to acute leukemia. Hallmarks of MDS are peripheral blood cytopenias (especially anemia), frequently with hypercellular bone marrow, and dysplastic changes in one or more hematopoietic lineages. The wide variation in clinical presentation has confounded treatment strategies and hindered the development of new therapies.

RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years.

The pathogenesis of acute myeloid leukemia (AML) involves the cooperation of mutations promoting proliferation/survival and those impairing differentiation. The RAS pathway has been implicated as a key component of the proliferative drive in AML. We have screened AML patients, predominantly younger than 60 years and treated within 2 clinical trials, for NRAS (n = 1106), KRAS (n = 739), and HRAS (n = 200) hot-spot mutations using denaturing high-performance liquid chromatography or restriction fragment length polymorphism (RFLP) analysis.

Latency of onset of de novo myelodysplastic syndromes.

The latency of onset of de novo myelodysplastic syndromes (MDS) is unknown. We report a retrospective analysis of blood counts from patients with MDS and acute myeloid leukemia (AML), and demonstrate temporal differences in rates of change of hemoglobin concentration and mean cell volume within 2-3 years of diagnosis, indicative of the earliest evidence of disease.