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Keywords: stem cell transplantation; aplastic anaemia; bone marrow failure; haploidentical transplantation; congenital amegakaryocytic thrombocytopenia EN stem cell transplantation aplastic anaemia bone marrow failure haploidentical transplantation congenital amegakaryocytic thrombocytopenia e56 e58 3 07/01/21 20210701 NES 210701 Aplastic anaemia (AA) is defined as pancytopenia with a hypocellular bone marrow without any abnormal infiltrate or fibrosis.1 Haematopoietic stem cell transplantation (HSCT) is the only curative option for both inherited bone marrow failure syndromes (BMFs) and acquired AA (aAA) in children.2 A routine therapeutic option in developed countries for many decades, the first allogeneic HSCT (allo-HSCT) to be performed in Sri Lanka was as recently as June 2014, for a child with transfusion-dependent thalassaemia (TdT). Case 1 and 4, with idiopathic AA underwent MSD HSCT following Flu/Cy/ATG conditioning. [Extracted from the article]

The article presents a study that investigated a serological surrogate for bone marrow assessment to optimise patient management and the patient experience. It discussed the findings to demonstrate a potential use for performed serological tests as surrogate markers for bone marrow minimal residual disease (MRD) negativity. It mentions the Isotype and International Staging System (ISS) distribution, median marrow plasma cell involvement, and median lactate dehydrogenase levels.

Mass cytometry in POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) syndrome: looking for a needle in a haystack In their current paper, Kourelis I et al i . profile the different immune cells within the bone marrow (BM) of patients with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) (Kourelis I et al. i , [8]). Different immune checkpoint regulators are expressed by HRS cells, but PD-L1 is found to be universally present on HRS cells due to a genetic amplification at chromosome 9 (De Goycoechea I et al. i , [6]). [Extracted from the article]

Entospletinib is also able to induce cell death I in vitro i in ETV6:RUNX1-derived cell lines, and is again stronger in this respect than fostamatinib.[14] Together, the data strongly support that the I ETV6:SYK i tyrosine kinase gene fusion is the driver underlying this clinicobiological entity. Spleen tyrosine kinase (SYK), a 72 kDa cytoplasmic non-receptor protein tyrosine kinase, is expressed primarily in haematopoietic cells like B-cells, monocytes, macrophages, mast cells, and neutrophils. [Extracted from the article]

In adult acute myeloid leukaemia (AML), immunophenotypic differences enable discrimination of leukaemic stem cells (LSCs) from healthy haematopoietic stem cells (HSCs). However, immunophenotypic stem cell characteristics are less explored in paediatric AML. Employing a 15‐colour flow cytometry assay, we analysed the expression of eight aberrant surface markers together with BCL‐2 on CD34+CD38− bone marrow stem cells from 38 paediatric AML patients and seven non‐leukaemic, age‐matched controls. Furthermore, clonality was investigated by genetic analyses of sorted immunophenotypically abnormal stem cells from six patients. A total of 50 aberrant marker positive (non‐HSC‐like) subsets with 41 different immunophenotypic profiles were detected. CD123, CLEC12A, and IL1RAP were the most frequently expressed markers. IL1RAP, CD93, and CD25 expression were not restricted to stem cells harbouring leukaemia‐associated mutations. Differential BCL‐2 expression was found among defined cytogenetic subgroups. Interestingly, only immunophenotypically abnormal non‐HSC‐like subsets demonstrated BCL‐2 overexpression. Collectively, we observed pronounced immunophenotypic heterogeneity within the stem cell compartment of paediatric AML patients. Additionally, certain aberrant markers used in adults seemed to be ineligible for detection of leukaemia‐representing stem cells in paediatric patients implying that inference from adult studies must be done with caution. [ABSTRACT FROM AUTHOR]

Summary: Multiple myeloma (MM) is characterized by malignant plasma cell infiltration of the bone marrow. In extramedullary multiple myeloma (EMD), a subclone of these cells migrates out of the bone marrow. Out of 4 985 MM patients diagnosed between 2005 and 2017 in the Czech Republic, we analyzed 234 secondary EMD patients to clarify risk factors of secondary EMD development. We found younger age [<65 years; odds ratio (OR) 4·38, 95% confidence interval (CI): 2·46–7·80, P < 0·0001], high lactate dehydrogenase (LDH) levels (>5 μkat/l; OR 2·07, 95% CI: 1·51–2·84, P < 0·0001), extensive osteolytic activity (OR 2·21, 95% CI: 1·54–3·15, P < 0·001), and immunoglobulin A (IgA; OR 1·53, 95% CI: 1·11–2·11, P = 0·009) or the non‐secretory type of MM (OR 2·83; 95% CI: 1·32–6·04, P = 0·007) at the time of MM diagnosis to be the main risk factors for secondary EMD development. Newly diagnosed MM (NDMM) patients with subsequent EMD had inferior median progression‐free (PFS) and overall (OS) survival when compared to NDMM patients without future EMD [mPFS: 13·8 months (95% CI: 11·4–16·3) vs 18·8 months (95% CI: 17·7–19·9), P = 0·006; mOS: 26·7 months (95% CI: 18·1–35·4) vs 58·7 months (95% CI: 54·8–62·6), P < 0·001]. We found that NDMM patients with specific risk factors associated with secondary EMD development have a more aggressive disease course before secondary EMD develops. [ABSTRACT FROM AUTHOR]

An eltrombopag-induced remission of bone-marrow aplasia accompanied by marked leukoerythroblastosis and splenomegaly Bone-marrow (BM) failure is caused by various mechanisms, including immune destruction of haematopoietic stem progenitor cells (HSPCs) and intrinsic abnormalities of these cells.1 Although pancytopenia with fatty BM is a sign suggestive of aplastic anaemia (AA), benign BM failure such as AA is commonly ruled out when leukoerythroblastosis is evident in the peripheral blood (PB). This study reports the clinical courses of two recently experienced cases [a 25-year-old woman (Case 1) and a 45-year-old-man (Case 2)] of BM failure, experiencing severe BM aplasia that was associated with marked leukoerythroblastosis in the PB and mild hepatosplenomegaly; a sustained remission of the atypical BM failure was induced by eltrombopag in Case 1. [Extracted from the article]

Summary: Deletion of the long arm of chromosome 6 (del6q) is the most frequent cytogenetic abnormality in Waldenström macroglobulinaemia (WM), occurring in approximately 50% of patients. Its effect on patient outcome has not been completely established. We used fluorescence in situ hybridisation to analyse the prevalence of del6q in selected CD19+ bone marrow cells of 225 patients with newly diagnosed immunoglobulin M (IgM) monoclonal gammopathies. Del6q was identified in one of 27 (4%) cases of IgM‐monoclonal gammopathy of undetermined significance, nine of 105 (9%) of asymptomatic WM (aWM), and 28/93 (30%) of symptomatic WM (sWM), and was associated with adverse prognostic features and higher International Prognostic Scoring System for WM (IPSSWM) score. Asymptomatic patients with del6q ultimately required therapy more often and had a shorter time to transformation (TT) to symptomatic disease (median TT, 30 months vs. 199 months, respectively, P < 0·001). When treatment was required, 6q‐deleted patients had shorter progression‐free survival (median 20 vs. 47 months, P < 0·001). The presence of del6q translated into shorter overall survival (OS), irrespective of the initial diagnosis, with a median OS of 90 compared with 131 months in non‐del6q patients (P = 0·01). In summary, our study shows that del6q in IgM gammopathy is associated with symptomatic disease, need for treatment and poorer clinical outcomes. [ABSTRACT FROM AUTHOR]

A novel KMT2A-USO1 fusion gene-induced de novo secondary acute myeloid leukaemia in a patient initially diagnosed with acute promyelocytic leukaemia Keywords: secondary acute myeloid leukemia; acute promyelocytic leukemia; KMT2A-USO1; clonal evolution; pre-leukemic event EN secondary acute myeloid leukemia acute promyelocytic leukemia KMT2A-USO1 clonal evolution pre-leukemic event e32 e36 5 12/21/20 20210101 NES 210101 The question whether secondary acute myeloid leukaemia (sAML) originates from a newly acquired or pre-existing clone has not been resolved for decades. Most cases of sAML are generally considered as therapy-related leukaemia,1 especially those with chromosomal translocations at 11q23 that involve the I KMT2A i gene (also known as I MLL i ).2,3 Here, we describe a 62-year-old male who was initially diagnosed with acute promyelocytic leukaemia (APL) carrying t(15;17)(q24;q21)/ I PML-RAR i . We found that KMT2A-USO1 also harboured the common characteristics of KMT2A fusions in significantly upregulating HOXA cluster genes ( I HOXA9 i and I HOXA10 i ) and the HOX coregulator gene I PBX3 i (Fig 1F). [Extracted from the article]

Summary: Multiple myeloma (MM) is characterised by the proliferation and accumulation of malignant plasma cells in the bone marrow. Despite the progress in treatment over the last few years, MM remains incurable and the majority of patients relapse. MM stem‐like cells (MMSCs) have been considered as the main reason for drug resistance and eventual relapse. Currently, therapeutic agents are not enough to eradicate MMSCs, and finding effective strategies to eradicate MMSCs may improve the outcome of patients. Here we showed that lycorine, a natural compound from the Amaryllidaceae species, effectively inhibits the proliferation of myeloma cells from cell lines or patients, mainly through decreasing ALDH1+ cells. Mechanistically, lycorine decreases the MMSC population through inhibition of the Wnt/β‐catenin pathway by reducing the β‐catenin protein level. Moreover, lycorine could overcome the increasing proportion of ALDH1+ cells caused by bortezomib (BTZ) treatment, and a combination BTZ and lycorine have a synergistic effect on anti‐myeloma cells. Furthermore, we found a similar reduction of MMSC characteristics by lycorine in BTZ‐resistant MM cells and primary CD138+ plasma cells. Collectively, our findings indicate lycorine as a promising agent to target MMSCs to overcome the drug resistance of BTZ, and that, alone or in combination with BTZ, lycorine is a potential therapeutic strategy for MM treatments. [ABSTRACT FROM AUTHOR]

Keywords: platelet aggregation; platelet disorders; platelet genetic diseases; platelet membrane; thrombocytopenia Flow cytometry labelling was realized on platelet-rich plasma obtained after centrifugation for the control and after whole-blood sedimentation for the patient because of the platelets' size. Platelets' patient were negative for GpIX (C, right) like immunolabelling of GpIb/IX/V complex of patients' megakaryocytes (D, lower) whereas control platelets (C, left) and megakaryocytes (D, upper) were positive. gl Platelet aggregation, platelet disorders, platelet genetic diseases, platelet membrane, thrombocytopenia. [Extracted from the article]

Summary: Patients with low‐risk myelodysplastic syndromes (MDS) usually develop iron overload. This leads to a high level of oxidative stress in the bone marrow (BM) and increases haematopoietic cell dysfunction. Our objective was to analyse whether chelation with deferasirox (DFX) alleviates the consequences of oxidative stress and improves BM cell functionality. We analysed 13 iron‐overloaded MDS patients' samples before and 4–10 months after treatment with DFX. Using multiparametric flow cytometry analysis, we measured intracellular reactive oxygen species (ROS), DNA oxidation and double strand breaks. Haematopoietic differentiation capacity was analysed by colony‐forming unit (CFU) assays. Compared to healthy donors, MDS showed a higher level of intracellular ROS and DNA oxidative damage in BM cells. DNA oxidative damage decreased following DFX treatment. Furthermore, the clonogenic assays carried out before treatment suggest an impaired haematopoietic differentiation. DFX seems to improve this capacity, as illustrated by a decreased cluster/CFU ratio, which reached values similar to controls. We conclude that BM cells from MDS are subject to higher oxidative stress conditions and show an impaired haematopoietic differentiation. These adverse features seem to be partially rectified after DFX treatment. [ABSTRACT FROM AUTHOR]

The article presents the research conducted by scientist Augusta Di Savino and others on the clinical significance of transferrin receptor 2 (TFR2) and erythropoietin receptor (EPOR) expression in bone marrow cells in patients with myelodysplastic syndromes. It mentions that TFR2alpha and TFR2beta expression was positively correlated with that of EPOR and patients with very low/low TFR2alpha or TFR2beta expression levels had a significantly worse overall survival.

The article focuses on the clinical trial conducted for patients diagnosed with chronic lymphocytic leukaemia (CLL) and thrombocytopenia with eltrombopag. It talks about the medication Eltrombopag being approved for the treatment of CLL as the immunosuppressive therapy and the standard therapy was unresponsive.

Multiple myeloma, inducible T-cell co-stimulator (ICOS), ICOS ligand (ICOSL), soluble ICOS, soluble ICOSL, osteopontin Keywords: multiple myeloma; inducible T-cell co-stimulator (ICOS); ICOS ligand (ICOSL); soluble ICOS; soluble ICOSL; osteopontin EN multiple myeloma inducible T-cell co-stimulator (ICOS) ICOS ligand (ICOSL) soluble ICOS soluble ICOSL osteopontin 1288 1289 2 03/22/22 20220315 NES 220315 INTRODUCTION Multiple myeloma (MM) is a cancer of bone marrow plasma cells that often develops from premalignant monoclonal gammopathy of undetermined significance (MGUS) through an intermediate stage known as smouldering multiple myeloma (SMM).1,2 MGUS and SMM are asymptomatic, whereas symptomatic patients with MM have one or more CRAB criteria (hypercalcaemia, renal failure, anaemia, and/or bone lesions). Inducible T-cell co-stimulator (ICOS) and ICOS ligand are novel players in the multiple-myeloma microenvironment. [Extracted from the article]

The article describes two cases of triple-refractory multiple myeloma (MM) treated with daratumumab (Dara), a first-in-class anti-CD38 humanized antibody. Bone marrow (BM) cells were treated with different doses to determine the effect of Dara on viability, CD38 and CD138 expression. The results indicate the in vitro and in vivo susceptibility of malignant cells taken from MM patients to Dara.

Although the majority of B cells express surface CD20 in chronic lymphocytic leukaemia (B- CLL), only ∼50% of patients respond to treatment with rituximab. Decreased CD20 expression on these tumour B cells could be responsible for the lack of response observed in some patients treated with rituximab. Despite the potential critical role of CD20 in the biology of B cell malignancies, the mechanisms controlling its expression are poorly understood. At the bone marrow level, mesenchymal stromal cells ( MSC) may regulate and support the survival of malignant cells, such as B- CLL cells. In this study, we investigated whether MSC may regulate the CD20 expression on B- CLL. For this purpose, B cells from CLL patients were isolated and co-cultured on MSC. B- CLL cells were collected from B- CLL/ MSC co-cultures and examined for their expression of CD20. We demonstrate decreased CD20 expression in B- CLL cells after 2 weeks of co-culture with MSC, under contact and non-contact conditions, which was associated with a decreased susceptibility to rituximab. Additionally, B cells co-cultured with MSCs show an increase in CD59 expression. Our findings strongly suggest that the interaction between B- CLL cells and MSC may play a major role in the resistance to rituximab-induced apoptosis of B- CLL cells. [ABSTRACT FROM AUTHOR]

Severe congenital neutropenia (SCN) was first clinically described in 1956 by Swedish pediatrician Rolf Kostmann, who recognized that infants who suffered from severe bacterial infections with absolute neutrophil counts (ANC) persistently below 0.5 × 10 SP 9 sp /l represented an inherited genetic disorder.1 SCN is now known to be caused by mutations in at least 25 genes and has autosomal recessive (AR), autosomal dominant (AD) and X-linked forms.2 The most common cause is due to AD mutations in the neutrophil elastase gene, I ELANE i , while the original disease Kostmann described was found to be due to AR mutations in I HAX1 i .3,4 Many of the genes causing SCN appear to be involved in endoplasmic reticulum (ER) or mitochondrial function and their disruption is involved in increasing ER stress and enhancing neutrophil apoptosis. Severe congenital neutropenia-associated JAGN1 mutations unleash a calpain-dependent cell death program in myeloid cells. JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. [Extracted from the article]