The recently developed International Consensus (IC) classification of hematologic neoplasms is primarily based on input from clinical advisory committees composed of pathologists, hematologists, oncologists, and genomic scientists. Morphology continues to represent a fundamental element in the definition of hematologic neoplasms. Acknowledging that the abnormal morphology is a result of dysregulated

Developing erythroblasts acquire massive amounts of iron through the transferrin (Tf) cycle, which involves endocytosis, sorting, and recycling of the Tf-Tf receptor (Tfrc) complex. Previous studies on the hemoglobin-deficit (hbd) mouse have shown that the exocyst complex is indispensable for the Tfrc recycling, however, the precise mechanism underlying the efficient exocytosis and recycling of Tfrc

Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the most effective treatment for selected patients with acute myeloid leukemia (AML) and relies on a "graft-versus-leukemia" effect (GVL) where donor T lymphocytes mediate control of malignant cell growth. However, relapse remains the major cause of death after allo-HSCT. In various malignancies, several immunoregulatory mechanisms have

Molecular programs initiating cell fate divergence (CFD) are difficult to identify. Current approaches usually compare cells long after CFD initiation, therefore missing molecular changes at its start. Ideally, single cells which differ in their CFD molecular program but are otherwise identical are compared early in CFD. This is possible in diverging sister cells, which were identical until their mother's

Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma is a rare large B-cell lymphoma subtype that is characterized by a plasmablastic phenotype and an ALK gene fusion. ALK-positive large B-cell lymphoma is resistant to the first-generation ALK inhibitor crizotinib and uniformly fatal with few if any complete responses in the relapsed setting, where no long-term survivors have been reported

According to experts' guidelines, lymph node surgical excision (SE) is the standard of care for lymphoma diagnosis. However, core needle biopsy (CNB) has widely spread in the lymphoma diagnostic work-up over years. The aim of this study was i) to display the largest multicentric inventory of lymph nodes sampled either by CNB or SE in patients with suspected lymphoma and ii) to compare their diagnostic

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy causing ischemic organ impairment. Blacks are overrepresented in iTTP cohorts in the United States but racial disparities in iTTP outcomes and response to therapy have not been studied. Using the United States Thrombotic Microangiopathy (USTMA) Consortium iTTP Registry, we

Somatic mutations in UBA1 cause VEXAS (Vacuoles, E1 ubiquitin activating enzyme, X-linked, Autoinflammatory Somatic) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic

Disorders of coagulation, resulting in serious risks for bleeding, may be caused by autoantibody formation or by mutations in genes encoding coagulation factors. In the latter case, anti-drug antibodies may form against the clotting factor protein drugs used in replacement therapy, as is well documented in treatment of the X-linked disease hemophilia. Such neutralizing antibodies against factors VIII

The Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) performed a prospective multicenter study of TCR-αβ/CD19-depleted haploidentical HCT in children with acute leukemia and myelodysplastic syndrome (MDS) to determine 1-year disease free survival (DFS) and compare 2-year outcomes to other donor cell sources. Fifty-one patients 0.7-21 years old were enrolled; donors were killer immunoglobulin-like

The advent of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of refractory B-cell malignancies. Real-world evidence has highlighted the high incidence of hematological toxicity, including prolonged and profound cytopenia. Here, we present a case of bone marrow (BM) failure in a 57-year old man with DLBCL-type Richter transformation receiving tisagenlecleucel

von Willebrand Factor (VWF) is an adhesive glycoprotein that circulates in the blood as disulfide-linked concatemers and functions in primary hemostasis. The loss of long VWF concatemers is associated with the excess bleeding of type 2A von Willebrand (VW) disease. Formation of the disulfide bonds that concatemerize VWF requires VWF to self-associate into helical tubules, yet how the helical tubules

Patients with severe aplastic anemia (SAA) can have an unrecognized inherited bone marrow failure syndrome (IBMFS) due to phenotypic heterogeneity. We curated germline genetic variants in 104 IBMFS-associated genes from exome sequencing performed on 732 patients who underwent HCT between 1989-2015 for acquired SAA. Patients with pathogenic/likely pathogenic (P/LP) variants fitting known disease zygosity

Patients with hematologic malignancies and recipients of hematopoietic cell transplantation (HCT) are more likely to experience severe coronavirus disease 2019 (COVID-19) and have a higher risk of morbidity and mortality after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compared to the general population, these patients have suboptimal humoral responses to COVID-19

Hematopoietic stem cells (HSCs) manifest impaired recovery and self-renewal with a concomitant increase in differentiation when exposed to ambient air as opposed to physioxia. Mechanism(s) behind this distinction are poorly understood but have the potential to improve stem cell transplantation. Single cell RNA-seq of HSCs in physioxia revealed upregulation of HSC self-renewal genes, and downregulation

While venous thromboembolism (VTE) is an important treatment and disease-related complication in myeloma, a validated risk-prediction model including disease-specific variables such as cytogenetics or tumor burden is lacking. The aim of our study was to develop a new risk-prediction model for VTE in the context of modern anti-myeloma therapy. All consecutive patients diagnosed at Cleveland Clinic during

Patients with immunoglobulin light chain (AL) amyloidosis and stage IIIb cardiac involvement have a dismal outcome despite the introduction of novel treatments. However, a rapid hematologic response translates in better survival. We evaluated the impact of early cardiac response and its depth on outcome in 249 patients with newly-diagnosed stage IIIb cardiac AL amyloidosis. Hematologic and cardiac

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CAC) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians

The gamma-glutamyl carboxylase (GGCX) generates multiple carboxylated Glus (Glas) in vitamin K-dependent (VKD) proteins that are required for their functions. GGCX is processive, remaining bound to VKD proteins throughout the multiple Glu carboxylations, and this study reveals the essentiality of processivity to VKD protein function. GGCX mutants (V255M, S300F) whose combined heterozygosity causes

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a protein tyrosine phosphatase and negatively regulates T cell signaling. However, whether it is expressed and functions in platelets remains unknown. Here we investigated the expression and role of PTPN22 in platelet function. We showed PTPN22 expression in both human and mouse platelets. Using PTPN22-/- mice, we demonstrated that PTPN22

Adult hematopoietic stem cells (HSCs) are predominantly quiescent and can be activated in response to acute stress such as infection or cytotoxic insults. STAT1 is a pivotal downstream mediator of interferon (IFN) signaling and is required for IFN-induced HSC proliferation, but little is known about the role of STAT1 in regulating homeostatic hematopoietic stem/progenitor cells (HSPCs). Here we show

Children's Oncology Group trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classical Hodgkin lymphoma. We investigated the impact of PET response after 1 cycle (PET1) and IFRT on outcomes and relapse pattern. Patients on AHOD 0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide)

Calreticulin (CALR) mutations are frequent, disease-initiating events in myeloproliferative neoplasms (MPN). Although the biological mechanism by which CALR mutations cause MPN has been elucidated, there currently are no clonally selective therapies for CALR-mutant MPN. To identify unique genetic dependencies in CALR-mutant MPN, we performed a whole-genome CRISPR knockout depletion screen in mutant

Unique molecular vulnerabilities have been identified in the aggressive MCD/C5 genetic subclass of diffuse large B cell lymphoma (DLBCL). However, the pre-malignant cell-of-origin exhibiting MCD-like dependencies remains elusive. In this study, we examined animals carrying up to four hallmark genetic lesions found in MCD consisting of gain-of-function mutations in Myd88 and Cd79b, loss of Prdm1 and

This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 inhibitor, with conventional care regimens (CCR) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive

Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of pro-inflammatory cytokines, including interleukin-1 beta (IL-1B). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated

Individuals with age-related clonal hematopoiesis (CH) are at greater risk for hematologic malignancies and cardiovascular diseases. However, predictive preclinical animal models to recapitulate the spectrum of human CH are lacking. Through error-corrected sequencing of 56 human CH/myeloid malignancy genes we identified natural CH driver mutations in aged rhesus macaques matching genes somatically

Sickle cell disease (SCD) is an inherited hemolytic anemia caused by a single point mutation in the beta‑globin gene of hemoglobin that leads to synthesis of sickle hemoglobin (HbS) in red blood cells (RBCs). HbS polymerizes in hypoxic conditions, leading to intravascular hemolysis, release of free hemoglobin and heme, and increased adhesion of blood cells to endothelial vasculature, which causes painful

Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drive inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer which upregulates transcription of EVI1. Here we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 which is frequently present in inv(3)/t(3;3)

Venetoclax inhibits the pro-survival protein BCL2 to induce apoptosis and is a standard therapy for chronic lymphocytic leukemia (CLL), delivering high complete remission rates and prolonged progression-free survival in relapsed CLL, but with eventual loss of efficacy. A spectrum of sub-clonal genetic changes associated with venetoclax resistance have now been described. To fully understand clinical