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In the second wave 57.8% (37/64) of patients received dexamethasone, 39.6% (25/64) of patients received remdesivir and one patient received tocilizumab. Patients with hematological malignancies who contract COVID-19 have been identified as having a high overall mortality rate of between 33 and 37% in a number of large studies from the first wave of COVID-19 infections in the first half of 2020 [[1], [3]]. In terms of hematological diagnoses, 34 patients had a lymphoid malignancy, 23 patients had a myeloid malignancy and 12 patients had a plasma cell disorder. Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients. [Extracted from the article]

Myeloid leukaemia of Down syndrome (ML‐DS) is an acute megakaryoblastic/erythroid leukaemia uniquely found in children with Down syndrome (constitutive trisomy 21). It has a unique clinical course, being preceded by a pre‐leukaemic condition known as transient abnormal myelopoiesis (TAM), and provides an excellent model to study multistep leukaemogenesis. Both TAM and ML‐DS blasts carry acquired N‐terminal truncating mutations in the erythro‐megakaryocytic transcription factor GATA1. These result in exclusive production of a shorter isoform (GATA1s). The majority of TAM cases resolve spontaneously without the need for treatment; however, around 10% acquire additional cooperating mutations and transform to leukaemia, with differentiation block and clinically significant cytopenias. Transformation is driven by the acquisition of additional mutation(s), which cooperate with GATA1s to perturb normal haematopoiesis. [ABSTRACT FROM AUTHOR]

Abstract: Spinal muscular atrophy (SMA) is a common neurodegenerative disease that is caused by mutations in the survival of motor neuron gene (SMN), leading to reduced levels of the SMN protein in affected individuals. In SMA, motor neurons selectively degenerate, however, the mechanism of cell death and the precise role of SMN in this process are not completely understood. In this study, we apply RNA interference (RNAi) to knockdown Smn gene expression in the murine embryonal carcinoma stem cell line P19, which can be differentiated into neuronal cells. A direct effect of Smn loss on apoptotic cell death in differentiated P19 neuronal cells, and to a lesser extent in undifferentiated cells was observed. Apoptosis could be partly reversed by expression of an SMN rescue construct, was reversible by the addition of the caspase-inhibitor ZVAD-fmk and involved the cytochrome c pathway. This study shows for the first time that knockdown of SMN results in apoptosis in mammalian neuronal cells and has implications for understanding the cause of motor neuron-specific cell loss in SMA, and for identifying novel therapeutic targets for this disease. [Copyright &y& Elsevier]

Children with Down syndrome (DS) up to the age of 4 years are at a 150-fold excess risk of developing myeloid leukemia (ML-DS). Approximately 4%-5% of newborns with DS develop transient myeloproliferative disorder (TMD). Blast cell structure and immunophenotype are similar in TMD and ML-DS. A mutation in the hematopoietic transcription factor GATA1 is present in almost all cases. Here, we show that simple techniques detect GATA1 mutations in the largest series of TMD (n = 134; 88%) and ML-DS (n = 103; 85%) cases tested. Furthermore, no significant difference in the mutational spectrum between the 2 disorders was seen. Thus, the type of GATA1 sequence mutation is not a reliable tool and is not prognostic of which patients with TMD are probable to develop ML-DS. [ABSTRACT FROM AUTHOR]

Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1 ; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS. • Genetic and functional analyses of myeloid preleukemia and leukemia in Down syndrome • Non-GATA1 preleukemic mutations are often not required for preleukemia • Previously undescribed transforming hotspot mutation in CSF2RB identified • Loss of function of 18 genes validated in transformation of preleukemia to leukemia Myeloid leukemia in Down syndrome (ML-DS) evolves from transient abnormal myelopoiesis (TAM). Labuhn et al. show that trisomy 21 and GATA1 mutations are sufficient for the development of TAM. They further identify and functionally validate additional variants that drive TAM to ML-DS transformation. [ABSTRACT FROM AUTHOR]

The megakaryocyte/erythroid Transient Myeloproliferative Disorder (TMD) in newborns with Down Syndrome (DS) occurs when N-terminal truncating mutations of the hemopoietic transcription factor GATA1, that produce GATA1short protein (GATA1s), are acquired early in development. Prior work has shown that murine GATA1s, by itself, causes a transient yolk sac myeloproliferative disorder. However, it is unclear where in the hemopoietic cellular hierarchy GATA1s exerts its effects to produce this myeloproliferative state. Here, through a detailed examination of hemopoiesis from murine GATA1s ES cells and GATA1s embryos we define defects in erythroid and megakaryocytic differentiation that occur relatively late in hemopoiesis. GATA1s causes an arrest late in erythroid differentiation in vivo, and even more profoundly in ES-cell derived cultures, with a marked reduction of Ter-119 cells and reduced erythroid gene expression. In megakaryopoiesis, GATA1s causes a differentiation delay at a specific stage, with accumulation of immature, kit-expressing CD41hi megakaryocytic cells. In this specific megakaryocytic compartment, there are increased numbers of GATA1s cells in S-phase of cell cycle and reduced number of apoptotic cells compared to GATA1 cells in the same cell compartment. There is also a delay in maturation of these immature GATA1s megakaryocytic lineage cells compared to GATA1 cells at the same stage of differentiation. Finally, even when GATA1s megakaryocytic cells mature, they mature aberrantly with altered megakaryocyte-specific gene expression and activity of the mature megakaryocyte enzyme, acetylcholinesterase. These studies pinpoint the hemopoietic compartment where GATA1s megakaryocyte myeloproliferation occurs, defining where molecular studies should now be focussed to understand the oncogenic action of GATA1s.

Disease relapse is the major cause of treatment failure after allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML). To identify AML-associated genes prognostic of AML relapse post-allo-SCT, we resequenced 35 genes in 113 adults at diagnosis, 49 of whom relapsed. Two hundred sixty-two mutations were detected in 102/113 (90%) patients. An increased risk of relapse was observed in patients with mutations in WT1 ( P = .018), DNMT3A ( P = .045), FLT3 ITD ( P = .071), and TP53 ( P = .06), whereas mutations in IDH1 were associated with a reduced risk of disease relapse ( P = .018). In 29 patients, we additionally compared mutational profiles in bone marrow at diagnosis and relapse to study changes in clonal structure at relapse. In 13/29 patients, mutational profiles altered at relapse. In 9 patients, mutations present at relapse were not detected at diagnosis. In 15 patients, additional available pre-allo-SCT samples demonstrated that mutations identified posttransplant but not at diagnosis were detectable immediately prior to transplant in 2 of 15 patients. Taken together, these observations, if confirmed in larger studies, have the potential to inform the design of novel strategies to reduce posttransplant relapse highlighting the potential importance of post-allo-SCT interventions with a broad antitumor specificity in contrast to targeted therapies based on mutational profile at diagnosis., Competing Interests: Conflicts-of-interest disclosure: The authors declare no competing financial interests.

Our understanding of the perturbation of normal cellular differentiation hierarchies to create tumor-propagating stem cell populations is incomplete. In human acute myeloid leukemia (AML), current models suggest transformation creates leukemic stem cell (LSC) populations arrested at a progenitor-like stage expressing cell surface CD34. We show that in ∼25% of AML, with a distinct genetic mutation pattern where >98% of cells are CD34(-), there are multiple, nonhierarchically arranged CD34(+) and CD34(-) LSC populations. Within CD34(-) and CD34(+) LSC-containing populations, LSC frequencies are similar; there are shared clonal structures and near-identical transcriptional signatures. CD34(-) LSCs have disordered global transcription profiles, but these profiles are enriched for transcriptional signatures of normal CD34(-) mature granulocyte-macrophage precursors, downstream of progenitors. But unlike mature precursors, LSCs express multiple normal stem cell transcriptional regulators previously implicated in LSC function. This suggests a new refined model of the relationship between LSCs and normal hemopoiesis in which the nature of genetic/epigenetic changes determines the disordered transcriptional program, resulting in LSC differentiation arrest at stages that are most like either progenitor or precursor stages of hemopoiesis., (© 2016 Quek et al.)

Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality following allogenic haematopoietic stem-cell transplantation and thus the focus of much ongoing research. Despite considerable advances in our understanding of the pathophysiology, diagnosis and predisposing factors for both acute and chronic forms of the disease, a standardised therapeutic strategy is still lacking. There is good evidence for initial treatment of both acute and chronic forms of the disease with corticosteroid therapy. However, the most effective approach to steroid-refractory disease remains controversial, with current practice based mainly on smaller studies and varying considerably between local institutions. Timely diagnosis, multidisciplinary working and good supportive care, including infection prophylaxis, are clearly important in optimizing response and survival in such patients. It is hoped that in the future systematic research strategies and the identification of novel therapeutic targets may improve outcome further. The following review aims to outline some of the existing options for the treatment and management of acute and chronic GVHD.