Megakaryoblastic leukemia 1 (MKL1) promotes the regulation of essential cell processes, including actin cytoskeletal dynamics by co-activating serum response factor. Recently, the first human case with MKL1 deficiency, leading to a novel primary immunodeficiency, was identified. We report a second family with two siblings with a homozygous frameshift mutation in MKL1. The index case deceased as an

Hemophilia A, an X-linked bleeding disorder caused by deficiency of factor VIII (FVIII), is treated by protein replacement. Unfortunately, this regimen is costly due to the expense of producing recombinant FVIII as a consequence of its low-level secretion from mammalian host cells. FVIII expression activates the endoplasmic reticulum (ER) stress response, causes oxidative stress and induces apoptosis

Daratumumab is a human monoclonal antibody targeting CD38, an antigen uniformly expressed by plasma cells in multiple myeloma and light chain amyloidosis (AL). We report the results of a prospective multi-center, phase 2 study of daratumumab monotherapy in AL (NCT02816476). Forty previously treated AL patients with a difference between involved and uninvolved free light chains (dFLC) > 50 mg/L were

The TEMPI syndrome is a rare and acquired disorder characterized by five salient features: (1) telangiectasias, (2) elevated erythropoietin and erythrocytosis, (3) monoclonal gammopathy, (4) perinephric fluid collections and (5) intrapulmonary shunting. Complete resolution of symptoms following treatment with plasma cell-directed therapy supports the hypothesis that that monoclonal antibody is causal

There are unresolved questions regarding the association between persistent leukocytosis and risk of thrombosis and disease evolution in polycythemia vera (PV), as much of the published literature on the topic does not appropriately utilize repeated measures data or time-dependent modeling to answer these questions. To address this knowledge gap, we analyzed a retrospective database of 520 PV patients

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease (LPD). This disease is hypothesized to result from defective immune surveillance of EBV with most patients showing evidence of immune dysfunction despite no known primary immunodeficiency. Pathologically, LYG is graded by the number and density of EBV+ atypical B-cells and other characteristic

Daratumumab has shown promising first results in systemic light-chain amyloidosis (AL). We analyzed a consecutive series of 168 patients with advanced AL receiving either daratumumab/dexamethasone (DD, n=106) or daratumumab/bortezomib/dexamethasone (DVD, n=62). DD achieved a remission rate (RR) of 64% and a very good hematologic remission (VGHR) rate of 48% after three months. Median hematologic event-free

Erdheim-Chester disease (ECD) is characterized by the infiltration of tissues by foamy CD68+CD1a- histiocytes, with 1500 known-cases since 1930. Mutations activating the MAPK pathway are found in more than 80% of ECD patients, mainly the BRAFV600E activating mutation in 57-70% of cases, followed by MAP2K1 in close to 20%. The discovery of BRAF mutations and of other MAP kinase pathway alterations,

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome describing patients with severe systemic hyperinflammation. Characteristic features include unremitting fever, cytopenias, hepatosplenomegaly, and elevation of typical HLH biomarkers. Patients can develop hepatitis, coagulopathy, liver failure, central nervous system involvement, multi-organ failure, and other manifestations. The syndrome has a

Systemic mastocytosis (SM) has greatly benefited from the broad application of precision medicine techniques to hematolymphoid neoplasms. Sensitive detection of the recurrent KIT D816V mutation and use of next generation sequencing (NGS) panels to profile the genetic landscape of SM variants have been critical adjuncts to the diagnosis of SM, subclassification of SM, and development of clinical-molecular

Fanconi anemia (FA) is the most common genetic cause of bone marrow failure, and is caused by inherited pathogenic variants in any of 22 genes. Of these, only FANCB is X-linked. We describe a cohort of 19 children with FANCB variants, from 16 families of the International Fanconi Anemia Registry (IFAR). Those with FANCB deletion or truncation demonstrate earlier than average onset of bone marrow failure

Langerhans Cell Histiocytosis (LCH) is caused by clonal expansion of myeloid precursors that differentiate into CD1a+/CD207+ cells in lesions that leads to a spectrum of organ involvement and dysfunction. The pathogenic cells are defined by constitutive activation of the MAPK signaling pathway. Treatment of LCH is risk-adapted; patients with single lesions may respond well to local treatment, whereas

Castleman disease (CD) describes a group of at least four disorders that share a spectrum of characteristic histopathological features but have a wide range of etiologies, presentations, treatments, and outcomes. CD includes unicentric CD (UCD) and multicentric CD (MCD), the latter of which is divided into idiopathic MCD (iMCD), HHV8-associated MCD (HHV8-MCD), and POEMS-associated MCD. iMCD can be

Non-coding RNAs including small nucleolar RNAs (snoRNAs) play important roles in leukemogenesis but the relevant mechanisms remain incompletely understood. We performed snoRNA focused CRISPR-Cas9 knockout library screenings which targeted the entire snoRNAnome and corresponding host genes. The C/D box containing SNORD42A was identified as an essential modulator for AML cell survival and proliferation

Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. While endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, it also subjects FVIII to a half-life ceiling of

We previously reported durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) patients treated with CD19-targeted chimeric antigen receptor-engineered T (CD19 CAR-T) cell immunotherapy after ibrutinib failure. Since pre-clinical studies showed that ibrutinib could improve CAR-T cell antitumor efficacy and reduce cytokine release syndrome (CRS), we conducted a pilot study

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by complexes between platelet factor 4 (PF4) and heparin or other polyanions, but the risk of thrombosis extends beyond exposure to heparin implicating other PF4 partners. We recently reported that peri-thrombus endothelium is targeted by HIT antibodies, but the binding site(s) has not been identified. We now show that PF4

Human herpesvirus 6B (HHV-6B) frequently reactivates after allogeneic hematopoietic cell transplantation (HCT). There are no randomized studies of antiviral treatments to prevent HHV-6B reactivation. Brincidofovir has high in vitro activity against HHV-6B and other DNA viruses, but its in vivo activity for HHV-6B has not been demonstrated. We performed a post hoc analysis of a randomized controlled

Short telomeres have been linked to cancer risk, yet other evidence supports they are tumor suppressive. Here, we report cancer outcomes in individuals with germline mutations in telomerase and other telomere maintenance genes. Among 180 individuals evaluated in a hospital-based setting, 12.8% had cancer. Solid tumors were rare (2.8%); nearly all were young male DKC1 mutation carriers, and they were

Targeted therapies for chronic lymphocytic leukemia (CLL) include venetoclax, the oral inhibitor of B cell lymphoma-2 (BCL2), and inhibitors of kinases in the B cell receptor signaling pathway, like Bruton's tyrosine kinase (BTK) and PI3-kinase. Randomized clinical trials clearly demonstrated improved progression-free survival with targeted therapy over chemoimmunotherapy in first-line and treatment

Promising activity of BET protein inhibitors (BETis) is compromised by adaptive or innate resistance in AML. Here, modeling of BETi-persister/resistance (BETi-P/R) in human post-MPN secondary AML (sAML) cells demonstrated accessible and active chromatin in specific super-enhancers/enhancers, which was associated with increased levels of nuclear β-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells

Human graft-versus-host disease (GvHD) biology beyond 3 months post-hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer (ABLE/PBMTC1202, NCT02067832) study evaluated the immune profiles in chronic GvHD (cGvHD) and late acute GvHD (L-aGvHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 after HSCT and correlated

Acute kidney injury (AKI) is a major clinical concern in sickle cell disease (SCD). Clinical evidence suggests that red cell alarmins may cause AKI in SCD however the sterile inflammatory process involved has hitherto not been defined. We discovered that hemopexin deficiency in SCD is associated with a compensatory increase in alpha-1-microglobulin (A1M) resulting in up to 10-fold higher A1M/hemopexin

c-Myc (Myc hereafter) is found to be deregulated and/or amplified in most acute myeloid leukemias (AML). Almost all AML cells are dependent upon Myc for their proliferation and survival. Thus Myc has been proposed as a critical anti-AML target. Myc has Max-mediated trans-activational and Miz1-mediated trans-repressional activities. The role of Myc-Max-mediated trans-activation in the pathogenesis of

T cell-mediated approaches have shown promise in myeloma treatment. However, there are currently a limited number of specific myeloma antigens that can be targeted, and MM remains an incurable disease. G-protein coupled receptor class 5 member D (GPRC5D) is expressed in multiple myeloma (MM) and smoldering multiple myeloma patient plasma cells. Here we demonstrate that GPRC5D protein is present on

In gene therapy with human hematopoietic stem and progenitor cells (HSPCs), each gene-corrected cell and its progeny are marked in a unique way by the integrating vector. This feature enables lineages to be tracked by sampling blood cells and using DNA sequencing to identify the vector integration sites. Here, we studied five cell lineages (granulocytes, monocytes, T cells, B cells, and natural killer

Expression of the cell cycle regulatory gene CDK6 is required for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) cell growth whereas expression of the closely related CDK4 protein is dispensable. Moreover, CDK6 silencing is more effective than treatment with the dual CDK4/6 inhibitor Palbociclib in suppressing Ph+ ALL in mice, suggesting that the growth-promoting effects of CDK6 are

Increasing evidence suggests that platelets play a predominant role in colon and breast cancer metastasis but the underlying molecular mechanisms remain elusive. Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin that triggers platelet activation through immunoreceptor tyrosine-based activation motif (ITAM)-signaling and thereby regulates diverse functions including platelet

Scleromyxedema is a rare skin and systemic mucinosis that is usually associated with monoclonal gammopathy (MG). In this French, multicenter, retrospective study of 33 patients, we investigated the clinical and therapeutic features of MG-associated scleromyxedema. Skin molecular signatures were analyzed using a transcriptomic approach. Skin symptoms included papular eruptions (100%), sclerodermoid

Treatment-related mortality is common among children with acute lymphoblastic leukemia (ALL) treated in poor-resource settings. We applied a simplified flow-cytometric assay to identify patients with precursor B-cell ALL (B-ALL) at very low risk (VLR) of relapse and treated them with a reduced-intensity treatment plan (RELLA05). VLR criteria include favorable presenting features (age ≥1 and <10 years)

Hematopoietic stem cell transplantation (HSCT) is often exploited to treat hematologic disease. Donor HSCs must survive, proliferate and differentiate in the damaged environment of the reconstituting niche. Illuminating molecular mechanisms regulating the activity of transplanted HSCs will inform efforts to improve HSCT. Here, we report that GPRASP proteins function as negative regulators of HSCT.

Bacterial infection not only stimulates innate immune responses but also activates the coagulation cascades. Over-activation of the coagulation system in bacterial sepsis leads to disseminated intravascular coagulation (DIC), a life-threatening condition. However, the mechanisms by which bacterial infection activates the coagulation cascade are not fully understood. Here we show that type 1 interferons

BACKGROUND The diagnosis of recurrent ipsilateral deep vein thrombosis (DVT) is challenging because persistent intravascular abnormalities after previous DVT often hinder a diagnosis by compression ultrasonography. Magnetic resonance direct thrombus imaging (MRDTI), a technique without intravenous contrast and with a 10-minute acquisition time, has been shown to accurately distinguish acute recurrent

The Src family kinases (SFKs) Src, Lyn and Fyn are essential for platelet activation and also involved in megakaryocyte (MK) development and platelet production. Platelet SFKs are inhibited by C-terminal Src kinase (Csk), which phosphorylates a conserved tyrosine in their C-terminal tail, and are activated by the receptor-type tyrosine phosphatase PTPRJ (CD148, DEP-1), which dephosphorylates the same

CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The extensively validated 30% of positive CLL cells cut-off value is able to separate CLL patients into two subgroups with different prognosis, but it does not consider the pattern of CD49d expression. In the present study, we analysed a cohort of 1,630 CLL samples and identified the presence of ~20% of CLL cases (n=313)