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We report on seven patients with myeloid diseases characterized by i(20q−) anomaly. Four patients were male and three were female, their median age was 57 years. The diagnosis at presentation was myelodysplastic syndrome in six patients, acute myeloid leukaemia in one patient. Four died but three survived and remain anaemic. The survivals were 6 months for patient 1, 7 months for patient 2, 17 d for patient 4 and 28 d for patient 5. Chromosome specimens were prepared by direct and/or short-term culture of bone marrow cells. Karyotype analysis was performed by R- and G-banding technique, which showed that one of the normal chromosomes 20 was substituted by one or two small metacentric chromosomes in all seven patients. The karyotype was ider(20)(q10)del(20)(q11q13), i.e. i(20q−) in six patients by dual-colour fluorescence in situ hybridization assay using two probes (a subtelomeric probe for 20q and an unique probe for 20q12). As far as we know, this anomaly has not been reported previously. Thus, we consider that i(20q−) is a novel and rare recurrent chromosomal abnormality that is specifically associated with myeloid diseases and may indicate a poor prognosis. [ABSTRACT FROM AUTHOR]

Haematopoietic progenitor cells proliferate and develop predominantly when they adhere to bone marrow stromal cells such as osteoblasts. Therefore, changes in adhesion may be a common mechanism by which stem cells survive, mature and properly traffic between the bone marrow and the circulation. To characterize these adhesion molecules, we reduced the bone marrow cavity to a simple adhesion assay between KG1a (a CD34+ haematopoietic cell line) and osteosarcoma monolayers (MG-63 or SaOS-2). The data demonstrated that adhesion was mediated by cell-to-cell rather than cell-to-matrix contact, was sensitive to trypsin, calcium chelators and glycosylation inhibitors. Selective pretreatment attributed the constitutive binding to N-linked glycans on KG1a. When carboprocessing was inhibited later at the high mannose intermediate (via deoxymannojirimycin), adhesion was retained. Surprisingly, binding of KG1a to SaOS-2 increased past constitutive levels as doses of tunicamycin or deoxymannojirimycin dropped. Selective pretreatment suggested that this ‘inducible’ binding resides with molecule(s) on SaOS-2. If the terminal sialic acid was digested (via neuraminidase), this induced response was duplicated. These data, verified in primary cells, suggest that the initial tethering between blood and bone cells in this model is probably due to heavily glycosylated, rapidly processed protein(s) on both cell types. [ABSTRACT FROM AUTHOR]

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.

Invasive fungal infections (IFIs) continue to cause considerable morbidity and mortality in haematopoietic stem cell transplant (HSCT) recipients. This review focuses on the risks for, and diagnosis of, IFIs (candidiasis, aspergillosis and other mould infections), and factors that affect current outcomes. Diagnosis of IFI is difficult, with the sensitivity of the gold standard tests (culture and histopathology) often <50%. Therefore, physicians rely on a constellation of clinical signs, radiography, culture, histopathology and adjunctive tests to establish diagnosis. HSCT recipients often have multiple co-morbidities, and understanding the current outcomes and prognostic variables is therefore important for overall management. This paper reviews historical trends and current data. [ABSTRACT FROM AUTHOR]

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]

CD34+ BM cells form a heterogenous population of primitive stem cells and more mature progenitors committed to different lineages of differentiation. By combining CD45 expression with SSC, it is possible to separate immature cells from more differentiated BM cells, and, by three-colour flow cytometry, analyse the antigens expressed in various subsets of cells. In this paper we show that in the normal BM at least four distinct CD34+ cell populations can be identified by their different patterns of CD45 expression and SSC. The most immature CD34+ cell population (0.1% of the BM cellularity) lacked all signs of lineage commitment and was CD45RA negative and only weakly CD45 positive. With increasing expression of the CD45 antigens, a second CD34+ population (0.2% of the BM cellularity) was formed expressing mainly primitive lymphatic antigens. However, 30% of the cells co-expressed B-cell line antigens and myeloid antigens. Cells committed to the myeloid cell line lost B-cell line antigens, gained CD45 antigen expression and SSC and formed two CD34+ cell populations (0.2% and 0.1% of the BM cellularity, respectively) differing only with respect to the pattern of myeloid antigen expression and SSC characteristics. Similarly, differentiation along the lymphatic pathway implicated down-regulation of myeloid antigens, loss of the stem cell antigen and immature lymphatic antigens and gain of CD45 expression and mature lymphatic antigens.

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]

The genetic basis of Diamond-Blackfan anaemia (DBA), a congenital erythroid hypoplasia that shows marked clinical heterogeneity, remains obscure. However, the fact that nearly one-quarter of patients harbour a variety of mutations in RPS19, a ribosomal protein gene, provides an opportunity to examine whether haplo-insufficiency of RPS19 protein can be demonstrated in certain cases. To that end, we identified 19 of 81 DBA index cases, both familial and sporadic, with RPS19 mutations. We found 14 distinct insertions, deletions, missense, nonsense and splice site mutations in the 19 probands, and studied mutations in 10 patients at the RNA level and in three patients at the protein level. Characterization of the mutations in 10 probands, including six with novel insertions, nonsense and splice site mutations, showed that the abnormal transcript was detectable in nine cases. The RPS19 mRNA and protein in CD34+ bone marrow cells identified haplo-insufficiency in three cases predicted to have one functional allele. Our data support the notion that, in addition to rare DBA patients with the deletion of one allele, the disease in certain other RPS19 mutant patients is because of RPS19 protein haplo-insufficiency. [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]

Platelets are the terminal differentiation product of megakaryocytes ( MKs). Cytokines, such as thrombopoietin ( TPO), are known to influence different steps in MK development; however, the complex differentiation and platelet localization processes are not fully understood. MKs express the receptor CXCR4 and have been shown to migrate in response to CXCL12 and to increase their platelet production. In this study, we studied the role of CXCR4 in platelet production with the high affinity CXCR4 antagonist, BKT140. Single and sequential administration of BKT140 significantly increased the number of MKs and haematopoietic progenitors ( HPCs) within the bone marrow ( BM). Increased megakaryopoiesis was associated with increased platelet production. Single and sequential administration of BKT140 also increased the number of HPCs in the blood. In a model of 5-fluorouracil-induced thrombocytopenia, BKT140 significantly reduced the severity and duration of thrombocytopenia and cytopenia when administered before and after chemotherapy. Our results demonstrated that the CXCR4 antagonist, BKT140, mediated unique beneficial effects by stimulating megakaryopoiesis and platelet production. These results provide evidence for the possible therapeutic use of BKT140 for modulating platelet numbers in thrombocytopenic conditions. [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]

The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma ( MM), as defined by the current International Myeloma Working Group ( IMWG) criteria, in patients with immunoglobulin light chain amyloidosis ( AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0·27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0·005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL. [ABSTRACT FROM AUTHOR]

Interactions between the Bruton tyrosine kinase ( BTK) inhibitor PCI-32765 and the proteasome inhibitor (bortezomib) were examined in diffuse large-B cell lymphoma ( DLBCL) and mantle cell lymphoma ( MCL) cells, including those highly resistant to bortezomib. Co-administration of PCI-32765/bortezomib synergistically increased mitochondrial injury and apoptosis in germinal centre- or activated B-cell-like- DLBCL cells and in MCL cells. These events were accompanied by marked AKT and nuclear factor ( NF)-κB ( NFKB1) inactivation, down-regulation of Mcl-1 (MCL1), Bcl- xL ( BCL2L1), and XIAP, and enhanced DNA damage (e.g., γH2A.X formation) and endoplasmic reticulum ( ER) stress. Similar interactions were observed in highly bortezomib-resistant DLBCL and MCL cells, and in primary DLBCL cells. In contrast, PCI-32765/bortezomib regimens displayed minimal toxicity toward normal CD34+ bone marrow cells. Transfection of DLBCL cells with a constitutively active AKT construct attenuated AKT inactivation and significantly diminished cell death, whereas expression of an NF-κB 'super-repressor' (IκBαser34/36) increased both PCI-32765 and bortezomib lethality. Moreover, cells in which the ER stress response was disabled by a dominant-negative eIF2α construct were resistant to this regimen. Finally, combined exposure to PCI-32765 and bortezomib resulted in more pronounced and sustained reactive oxygen species ( ROS) generation, and ROS scavengers significantly diminished lethality. Given promising early clinical results for PCI-32765 in DLBCL and MCL, a strategy combining BTK/proteasome inhibitor warrants attention in these malignancies. [ABSTRACT FROM AUTHOR]

To analyse the outcome of adult patients who developed a first relapse of acute lymphoblastic leukaemia ( ALL), we collected the clinical data of 332 patients with Philadelphia-chromosome (Ph) negative ALL, aged 16-65 years, who relapsed after first complete remission ( CR1) between 1998 and 2008 in 69 institutions all over Japan, including 58 patients who relapsed after allogeneic haematopoietic stem cell transplantation (Allo- HSCT) in CR1. The overall survival ( OS) was 43·4% at 1 year, and 16·3% at 5 years from relapse in patients who received chemotherapy alone in CR1. Among patients who relapsed after chemotherapy alone in CR1, 123 (52·5%) achieved a second remission ( CR2) following salvage chemotherapy, of whom 62 subsequently underwent Allo- HSCT during CR2. Allo- HSCT in CR2 was significantly associated with better OS. Moreover, the type of salvage chemotherapy influenced OS from relapse. A doxorubicin, vincristine, and predonisone-based (Ad VP-type) regimen was related to better OS in patients with longer CR1 (more than 1 year), but was related to worse OS in patients with shorter CR1. In conclusion, the prognosis of patients with relapsed Ph-negative ALL is poor. Allo- HSCT after a first relapse could improve the prognosis. Selection of the optimal salvage chemotherapy might depend on the duration of CR1. [ABSTRACT FROM AUTHOR]

Although TNFRSF17 (also designated as B-cell maturation antigen (BCMA)) is expressed on tumour cells in B-cell malignancies, it has not been found in serum. The present study found that BCMA concentrations were higher in the supernatants of cultured bone marrow mononuclear cells from multiple myeloma ( MM) patients than in healthy subjects. Serum BCMA levels were measured in samples from MM patients ( n = 209), monoclonal gammopathy of undetermined significance ( MGUS) individuals ( n = 23) and age-matched controls ( n = 40). BCMA was detected in the serum of untreated MM patients ( n = 50) and levels were higher than in MGUS patients ( P = 0·0157) and healthy subjects ( P < 0·0001). Serum BCMA levels were higher among patients with progressive disease ( n = 80) compared to those with responsive disease ( n = 79; P = 0·0038). Among all MM patients, overall survival was shorter among patients whose serum BCMA levels were above the median ( P = 0·001). We also demonstrated that sera from mice with human MM xenografts contained human BCMA, and levels correlated with the change in tumour volume in response to melphalan or cyclophosphamide with bortezomib. These results suggest that serum BCMA levels may be a new biomarker for monitoring disease status and overall survival of MM patients. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is characterized by almost exclusive tropism of malignant cells for the bone marrow (BM) milieu. The survival and proliferation of malignant plasma cells have been shown to rely on interactions with nonmalignant stromal cells, in particular mesenchymal stromal cells (MSCs), in the BM microenvironment. However, the BM microenvironment is composed of a diverse array of cell types. This study examined the role of macrophages, an abundant component of BM stroma, as a potential niche component that supports malignant plasma cells. We investigated the proliferation of MM tumour cell lines when cultured alone or together with MSCs, macrophages, or a combination of MSCs and macrophages, using the carboxyfluorescein succinimidyl ester assay. Consistently, we observed increased proliferation of MM cell lines in the presence of either MSCs or macrophages compared to cell line-only control. Furthermore, the combined co-culture of MSCs plus macrophages induced the greatest degree of proliferation of myeloma cells. In addition to increased proliferation, MSCs and macrophages decreased the rate of apoptosis of myeloma cells. Our in vitro studies provide evidence that highlights the role of macrophages as a key component of the BM microenvironment facilitating the growth of malignant plasma cells in MM. [ABSTRACT FROM AUTHOR]

The article offers information on the children with juvenile myelomonocytic leukaemia (JMML) and the haematological improvement observed after the chemotherapy. It is suggested that allogeneic haematopoietic stem cell transplantation (HSCT) is only curative treatment for JMML. It also presents the chart related to the number of patients who showed long-term haematological improvement despite no chemotherapy or after non-intensive chemotherapy is indicated in parenthesis.

Myelofibrosis ( MF) is a heterogeneous disease for which long-term, effective medical therapeutic options are currently limited. The role of allogeneic haematopoietic stem cell transplant ( AHSCT) in this population, many of whom are elderly, often provides a challenge with regard to the identification of suitable candidates, timing of transplantation in the disease course and choice of conditioning regimen. This review summarizes key findings from published data concerning AHSCT in MF and attempts to provide a state of the art approach to MF- AHSCT in 2012. In addition, we postulate on how the era of JAK inhibition might impact on transplantation for MF. [ABSTRACT FROM AUTHOR]

Summary We retrospectively analysed the outcome of consecutive children with idiopathic severe aplastic anaemia in the United Kingdom who received immunosuppressive therapy ( IST) or matched unrelated donor ( MUD) haematopoietic stem cell transplantation ( HSCT). The 6-month cumulative response rate following rabbit antithymocyte globulin ( ATG)/ciclosporin ( IST) was 32·5% (95% CI 19·3-46·6) ( n = 43). The 5-year estimated failure-free survival ( FFS) following IST was 13·3% (95% confidence interval [ CI] 4·0-27·8). In contrast, in 44 successive children who received a 10-antigen ( HLA-A, -B, -C, - DRB1, - DQB1) MUD HSCT there was an excellent estimated 5-year FFS of 95·01% (95% CI 81·38-98·74). Forty of these children had failed IST previously. HSCT conditioning was a fludarabine, cyclophosphamide and alemtuzumab ( FCC) regimen and did not include radiotherapy. There were no cases of graft failure. Median donor chimerism was 100% (range 88-100%). A conditioning regimen, such as FCC that avoids total body irradiation is ideally suited in children. Our data suggest that MUD HSCT following IST failure offers an excellent outcome and furthermore, if a suitable MUD can be found quickly, MUD HSCT may be a reasonable alternative to IST. [ABSTRACT FROM AUTHOR]

Summary Patients with paroxysmal nocturnal haemoglobinuria (PNH) have expanded clonal cells bearing a somatic mutation in the PIGA gene. Our previous study on two PNH patients with chromosome 12 rearrangements demonstrated the involvement of HMGA2 expression in clonal expansion. The present study investigated HMGA2 expression in PNH patients without chromosomal abnormalities. The expression of short HMGA2 with latent exon was significantly high in peripheral blood cells from 18 of 24 patients. Over-expression of truncated HMGA2 in mouse bone marrow cells caused expansion in recipient mice. These results support the idea that deregulated expression of HMGA2 causes expansion of PNH cells. [ABSTRACT FROM AUTHOR]

B-catenin is the central effector molecule of the canonical Wnt signalling pathway, which controls self-renewal of haematopoietic stem cells. Deregulation of this pathway occurs in various malignancies including myeloid leukaemias. The present study examined the functional outcome of stable β-catenin down-regulation through lentivirus-mediated expression of short hairpin RNA (shRNA). Reduction of the β-catenin levels in acute myeloid leukaemia (AML) cell lines and patient samples decelerated their in vitro proliferation ability without affecting cell viability. Transplantation of leukaemic cells with control or reduced levels of β-catenin in non-obese diabetic severe combined immunodeficient animals indicated that, while the immediate homing of the cells was unaffected, the bone marrow engraftment was directly dependent on β-catenin levels. Subsequent examination of bone sections revealed that β-catenin was implicated in the localization of AML to the endosteum. Examination of adhesion molecule expression before and after transplantation, revealed down-regulation of CD44 expression, accompanied by reduced in vitro adhesion. Gene expression analysis disclosed the presence of an autocrine compensatory mechanism, which responds to the reduced β-catenin levels by altering the expression of positive and negative pathway regulators. In conclusion, our study showed that β-catenin comprises an integral part of AML cell proliferation, cell cycle progression, and adhesion, and influences disease establishment in vivo. [ABSTRACT FROM AUTHOR]

Shwachman-Diamond Syndrome (SDS) is a multi-system genetic disorder with bone marrow failure. SBDS, the gene associated with SDS, has been postulated to play a role in ribosome biogenesis and RNA processing, but its functions are still unknown. To study whether these pathways are interrupted when Sbds protein is lost, we studied the expression of related genes in patient SBDS−/− cells by an oligonucleotide microarray. We first analysed ribosomal protein (RP) genes, which are normally co-regulated. In SDS, 27 of the 85 RP genes were downregulated. Among the downregulated RP genes, seven are known to be associated with the inhibition of apoptosis. RPS27L, which mediates p53-dependent induction of apoptosis, was the only upregulated RP gene. Interestingly, several genes involved in RP mRNA transcription were downregulated without affecting the expression of genes involved in mRNA degradation, suggesting that the downregulation of the RP gene expression might be at the transcriptional level. Importantly we also found dysregulation of multiple genes involved in rRNA transcription and pre-rRNA processing. We conclude that SDS marrow cells exhibit major dysregulation of RP, RNA processing and RNA transcription genes. [ABSTRACT FROM AUTHOR]

Syndecan-1 is a proteoglycan that concentrates heparin-binding factors on the surface of multiple myeloma cells, and probably plays a major role in multiple myeloma biology. As heparan sulphate and chondroitin sulphate are the bioactive components of syndecan-1, we analysed the signature of genes encoding 100 proteins involved in synthesis of these chains, i.e. from precursor uptake to post-translational modifications, using Affymetrix microarrays. The expression of enzymes required for heparan sulphate and chondroitin sulphate biosynthesis was shown to increase in parallel with syndecan-1 expression, throughout the differentiation of memory B cells into plasmablasts and normal bone marrow plasma cells. Sixteen genes were significantly different between normal and malignant plasma cells, nine of these genes – EXT2, CHSY3, CSGALNACT1, HS3ST2, HS2ST1, CHST11, CSGALNACT2, HPSE, SULF2 – encode proteins involved in glycosaminoglycan chain synthesis or modifications. Kaplan–Meier analysis was performed in two independent series of patients: B4GALT7, CSGALNACT1, HS2ST1 were associated with a good prognosis whereas EXT1 was linked to a bad prognosis. This study provides an overall picture of the major genes encoding for proteins involved in heparan sulphate and chondroitin sulphate synthesis and modifications that can be implicated in normal and malignant plasma cells. [ABSTRACT FROM AUTHOR]

In this study six versions of recombinant human hoxb4 proteins were produced and their effectiveness evaluated in expanding human haematopoietic stem and progenitor cells in vitro and in vivo. An N-terminal-tat and C-terminal histidine-tagged version of hoxb4 (T-hoxb4-H) showed the highest activity in expanding colony forming cells (CFCs) and long-term culture-initiating cells (LTC-ICs) when used at 50 nmol/l concentration in cell culture. Human cord blood CD34+ cells cultured with 50 nmol/l T-hoxb4-H showed a significant increase in severe-combined immunodeficient mouse-repopulating cells (SRCs). In a mouse model of immune-mediated bone marrow (BM) failure, T-hoxb4-H showed an additive effect with cyclosporine in alleviating pancytopenia. In addition, T-hoxb4-H expanded CFC and LTC-IC on BM samples from patients with refractory severe aplastic anaemia and myelodysplastic syndromes: after culturing with 50 nmol/l T-hoxb4-H for 4 d, BM cells from 10 of the 11 patients showed increases in CFC and LTC-IC, and the increase in LTC-IC was statistically significant in samples from four patients. Recombinant human hoxb4 could be a promising therapeutic agent for BM failure. [ABSTRACT FROM AUTHOR]

Nuclear factor-κB (NF-κB) has been implicated in a number of malignancies and has been suggested to be a potential molecular target in the treatment of leukaemia. This study demonstrated the constitutive activation of NF-κB in human myeloid blasts and a clear correlation between NF-κB expression and in vitro cytoprotection. High NF-κB expression was found in many of the poor prognostic acute myeloid leukaemia (AML) subtypes, such as French-American-British classification M0 and M7, and the poor cytogenetic risk group. The in vitro effects of LC-1, a novel dimethylamino-parthenolide analogue, were assessed in 62 primary untreated AML samples. LC-1 was found to be cytotoxic to AML cells in a dose-dependent manner, mediated through the induction of apoptosis. The median drug concentration necessary to kill 50% of the cells was 4·5 μmol/l for AML cells, compared with 12·8 μmol/l for normal marrow cells. LC-1 was shown to reduce the five individual human NF-κB Rel proteins in a dose-dependent manner. The subsequent inhibition of many NF-κB-regulated cytokines was also demonstrated. Importantly, sensitivity to LC-1 was correlated with the basal NF-κB activity. Consequently, LC-1 treatment provides a proof of principle for the use of NF-κB inhibitors in the treatment of AML. [ABSTRACT FROM AUTHOR]

The treatment of adults with Philadelphia-negative acute lymphoblastic leukaemia (ALL) depends on the presence of risk factors including age, white blood cell count, immunophenotype and time to complete remission. In recent years, status of minimal residual disease (MRD) has been postulated as an additional risk criterion. This study prospectively evaluated the significance of MRD. Patients were treated with a uniform Polish Adult Leukemia Group (PALG) 4-2002 protocol. MRD status was assessed after induction and consolidation by multiparametric flow cytometry. Out of 132 patients included (age, 17–60 years), 116 patients were suitable for analysis. MRD level ≥0·1% of bone marrow cells after induction was found to be a strong and independent predictor for relapse in the whole study population ( P < 0·0001), as well as in the standard risk (SR, P = 0·0003) and high-risk ( P = 0·008) groups. The impact of MRD after consolidation on outcome was not significant. The combination of MRD status with conventional risk stratification system identified a subgroup of patients allocated to the SR group with MRD <0·1% after induction who had a very low risk of relapse of 9% at 3 years as opposed to 71% in the remaining subjects ( P = 0·001). We conclude that MRD evaluation after induction should be considered with conventional risk criteria for treatment decisions in adult ALL. [ABSTRACT FROM AUTHOR]

Double-negative (DN) regulatory T cells (Tregs) are specialized T lymphocytes involved in the down-modulation of immune responses, resulting in allotolerance after allogeneic haematopoietic stem cell transplantation (HSCT). Most of the properties of DN Tregs were identified in murine models, including the unique ability to suppress alloreactive syngeneic effector T cells in an antigen-specific manner via Fas/Fas-ligand interactions. We investigated the behaviour of DN Tregs following human allogeneic HSCT with regard to occurrence of graft-versus-host disease (GvHD) and restoration of T-cell receptor repertoire in a cohort of 40 patients. The frequency of DN Tregs and CD4/CD8 TCR repertoire was measured serially and at the time of diagnosis of GvHD by flow cytometry. Analysis demonstrated a positive correlation between degree of alloreactivity, as measured by grade of GvHD, and the number of variable beta chain (Vβ) family expansions in both T-cell populations. We also found that a deficiency of DN Tregs was associated with an increased number of Vβ family expansions, and most importantly, with the occurrence of GvHD. All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT. [ABSTRACT FROM AUTHOR]

For children with severe aplastic anemia (SAA) who fail immunosuppressive therapy and lack a human leucocyte antigen (HLA)-matched sibling donor, unrelated donors provide a source of hematopoietic stem cells. Data from 195 children with acquired SAA who underwent unrelated donor transplantation between 1989 and 2003 were analyzed. Neutrophil recovery (86% at day-28) was higher with total body irradiation-containing conditioning regimen and in younger recipients (aged ≤16 years) receiving grafts from older donors (aged >40 years). Recovery was lower after mismatched transplants and transplantations prior to 1997. Mortality rates were higher after mismatched transplants, in recipients with a poor performance score, and when the interval between diagnosis and transplantation was longer than 4 years. When restricted to donor-recipient pairs with allele-level HLA typing (8-loci; n = 118), mortality rates were also higher after mismatched transplants and older recipients receiving grafts from older donors; 5-year probabilities of overall survival after HLA-A, -B, -C, -DRB1 matched and mismatched transplants adjusted for donor and recipient age were 57% and 39%, respectively ( P = 0·008). The data suggest that unrelated donor transplantation is an acceptable alternative for children; early referral for transplantation and identification of an HLA-matched (allele-level) donor offers the best outcome. [ABSTRACT FROM AUTHOR]

The role of haematopoietic stem cell transplantation (HSCT) in relapsed follicular lymphoma remains controversial. This study analysed 126 patients with relapsed, advanced stage follicular lymphoma who received BEAM (BCNU [carmustine], cytarabine, etoposide, melphalan)-alemtuzumab allogeneic HSCT (BEAM-allo) ( n = 44) or BEAM-autologous HSCT (BEAM-auto) ( n = 82). The BEAM-allo group had a younger median age (48 years vs. 56 years, P < 0·001) but received a higher median number of therapies pretransplant ( P = 0·015) compared with the BEAM-auto group. There was a higher non-relapse mortality (NRM) in the BEAM-allo group compared with the BEAM-auto group at 1 year (20% vs. 2%, P = 0·001). Older age and heavily pretreated patients were associated with a higher NRM and poorer survival in the BEAM-allo group. There was, however, a significantly lower relapse rate (20% vs. 43%, P = 0·01) at 3 years with BEAM-alemtuzumab, with no relapses after 2 years, compared with a continued pattern of relapse in the autologous group. No difference in overall survival (OS) ( P = 0·99) or disease-free survival (DFS) ( P = 0·90) was identified at 3 years, whereas a plateau in OS and DFS with crossing of the survival curves in favour of BEAM-allo group was observed. Furthermore, the ability to re-induce remissions with donor leucocytes provides additional benefit in favour of allogeneic HSCT. [ABSTRACT FROM AUTHOR]

Despite improved responses, chronic lymphocytic leukaemia (CLL) remains incurable with conventional chemotherapy. Patients with poor-risk factors or who fail conventional chemoimmunotherapy are offered autografts, preferably after achieving remission. This report presents the totality of evidence through a systematic review that assessed the efficacy of autografts in CLL. A search of MEDLINE databases from 1966–2006 and hand-search of references identified 82 prospective-randomized, non-randomized comparisons or single-arm trials, of which only nine met our inclusion criteria: two trials were funded by public/government, one by private foundations, one jointly by private/public, and was unclear in five. No randomized controlled trials comparing autografts versus conventional chemotherapy (or chemoimmunotherapy) were found. Six studies were single-arm and three were non-randomized with a control-arm (autologous versus allogeneic). Overall, 361 patients were enrolled, but only 292 were transplanted. Transplant-related mortality ranged from 0% to 9%. Complete responses ranged from 74% to 100% and molecular responses ranged from 57% to 88%. Overall survival ranged from 68% at 3 years to 58% at 6 years. It is uncertain whether autograft is superior to conventional therapy. The high incidence of myelodysplastic syndrome (9–12%) is particularly concerning in CLL, where median survival is 9 years. [ABSTRACT FROM AUTHOR]

The TLX/HOX11 subfamily of divergent homeobox genes are involved in various aspects of embryogenesis and, in the case of TLX1/HOX11 and TLX3/HOX11L2, feature prominently as oncogenes in human T-cell acute lymphoblastic leukaemia. TLX1 possesses immortalising activity in a wide variety of blood cell lineages, however, the effect of this oncogene on haemopoietic cell differentiation has not been fully investigated. We therefore constitutively expressed TLX1 in murine bone marrow or fetal liver cells using retroviral transfer followed by transplantation and/or in vitro culture. TLX1 was found to dramatically alter haemopoiesis, promoting the emergence of a non-haemopoietic CD45− CD31+ cell population while markedly inhibiting erythroid and granulocytic cell differentiation. To identify genetic programs perturbed by TLX1, a comparison of transcript profiles from J2E erythroid cells with and without enforced TLX1 expression was undertaken. This revealed a pattern of gene expression indicative of enhanced proliferation coupled to differentiation arrest. Of the genes identified, two, KIT and VEGFC, were found to be potential TLX1 targets based on transcriptional assays. These results demonstrate that TLX1 can act broadly to impair haemopoiesis and divert differentiation to an alternative fate. This may account for its ability to promote the pre-leukaemic state via perturbation of specific gene expression programs. [ABSTRACT FROM AUTHOR]

Shwachman–Diamond syndrome (SDS) is an inherited bone marrow failure disorder with cytopenia and a high propensity for myelodysplastic syndrome (MDS) and leukaemia, particularly acute myeloid leukaemia. The mechanism of leukaemogenesis in SDS is unknown. In accordance to the multi-hit theory of carcinogenesis, it is likely that several molecular and cellular hits occur before MDS/leukaemia become apparent. This study used oligonucleotide microarray to identify gene expression patterns, which were shown to be associated with leukaemogenesis, in marrow mononuclear cells of nine SDS patients without overt transformation compared to healthy controls. Among 154 known leukaemia-related genes, several oncogenes were found to be upregulated, including LARG, TAL1 and MLL, and of several tumour suppressor genes were downregulated, including DLEU1, RUNX1, FANCD2 and DKC1. Real time polymerase chain reaction confirmed statistically higher expression of LARG and TAL1 in SDS marrows. We conclude that SDS marrow mononuclear cells exhibit abnormal gene expression patterns, which might result in continuous stimulation favouring evolution or progression of malignant clones. Additional molecular and cytogenetic events are probably necessary for the malignant process to be irreversible and complete. [ABSTRACT FROM AUTHOR]

Hydroxycarbamide (HC) (or hydroxyurea) has been reported to increase fetal haemoglobin levels and improve clinical symptoms in sickle cell anaemia (SCA) patients. However, the complete pathway by which HC acts remains unclear. To study the mechanisms involved in the action of HC, global gene expression profiles were obtained from the bone marrow cells of a SCA patient before and after HC treatment using serial analysis of gene expression. In the comparison of both profiles, 147 differentially expressed transcripts were identified. The functional classification of these transcripts revealed a group of gene categories associated with transcriptional and translational regulation, e.g. EGR-1, CENTB1, ARHGAP4 and RIN3, suggesting a possible role for these pathways in the improvement of clinical symptoms of SCA patients. The genes involved in these mechanisms may represent potential tools for the identification of new targets for SCA therapy. [ABSTRACT FROM AUTHOR]

Patients with chronic idiopathic neutropenia (CIN) display relatively low peripheral blood platelet counts and hypo-lobulated megakaryocytes in the bone marrow (BM). The underlying pathogenetic mechanismswere probed by studying the reserves and clonogenic potential of BM megakaryocytic progenitor cells using flow-cytometry and a collagen-based clonogenic assay for the identification of megakaryocyte colony-forming units (CFU-Meg). Thrombopoietin (TPO) and transforming growth factor- β1 (TGF β1) levels were also evaluated in long-term BM culture supernatants using an enzyme-linked immunosorbent assay. CIN patients ( n = 39) showed a low proportion of BM CD34+/CD61+ megakaryocytic progenitor cells and low frequency of early and mixed CFU-Meg in the BM mononuclear, but not CD34+, cell fraction, compared with healthy controls ( n = 20). TPO and TGF β1 levels were significantly higher in patients compared with controls. TPO levels inversely correlated with platelet counts whereas TGF β1 values correlated inversely with CD34+/CD61+ and CFU-Meg megakaryocytic progenitor cell numbers and positively with TPO levels. The addition of an anti-TGF β1 neutralising antibody significantly increased the numbers of CFU-Meg in CIN patients but not in controls, compared with baseline. These data suggest that increased local production of TGF β1 probably affects the BM megakaryocytic progenitor cell growth in CIN whereas the compensatory production of TPO finally balances the TGF β1-induced inhibitory effect. [ABSTRACT FROM AUTHOR]

The efficacy of allogeneic haematopoietic stem-cell transplantation (allo-HSCT) for natural killer (NK)-cell neoplasms is unknown. We investigated the results of allo-HSCT for NK-cell neoplasms between 1990 and 2003 through questionnaires. After reclassification by a haematopathologist, of 345 patients who underwent allo-HSCT for malignant lymphoma, 28 had NK-cell neoplasms (World Health Organization classification): extranodal NK/T-cell lymphoma ( n = 22), blastic NK-cell lymphoma ( n = 3), and aggressive NK-cell leukaemia ( n = 3). Twelve were chemosensitive and 16 chemorefractory. Twenty-two had matched-related donors. Stem-cell source was bone marrow in eight and mobilised peripheral blood in 20. Conditioning regimens were myeloablative ( n = 23) and non-myeloablative ( n = 5). Grade 2–4 acute graft- versus-host disease (GVHD) and chronic GVHD developed in 12 and 8 respectively. Eight died of disease progression, three of infection, two of acute GVHD, one of veno-occlusive disease, one of interstitial pneumonitis, and one of thrombotic microangiopathy. Two-year progression-free and overall survivals were 34% and 40% respectively (median follow-up, 34 months). All patients who did not relapse/progress within 10 months achieved progression-free survival (PFS) during the follow-up. In multivariate analysis, stem cell source (BM versus peripheral blood; relative risk 3·03), age (≥40 years vs. <40 years; relative risk 2·85), and diagnoses (extranodal NK/T-cell lymphoma versus others; relative risk 3·94) significantly affected PFS. Allo-HSCT is a promising treatment for NK-cell neoplasms. [ABSTRACT FROM AUTHOR]

Familial haemophagocytic lymphohistiocytosis (FHLH) is a genetic disorder caused by defective lymphocyte cytotoxicity, resulting in impaired lymphocyte homeostasis and macrophage infiltration of solid tissues and bone marrow, with extensive haemophagocytosis. It is invariably fatal unless treated by allogeneic haematopoietic stem cell transplantation (HSCT). In a retrospective analysis of 11 cases of FHLH, transplanted in one centre between January 1999 and December 2003, it was found that host T cell expansion occurred early after HSCT in a setting of a viral infection (cytomegalovirus and Epstein–Barr virus respectively) in two cases who received T cell-depleted HSCT. Transient recurrence of clinical and biological manifestations of FHLH was observed, despite evidence for donor cell engraftment. Secondary development of donor T cells led to stable mixed chimaerism and sustained remission of FHLH. Detection of host-derived T cells soon after HSCT in a patient with FHLH should thus not mistakenly be taken as a manifestation of graft rejection. [ABSTRACT FROM AUTHOR]