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Key Points Fetal injection of antibodies against the c-Kit receptor and CD47 effectively depletes host HSCs in immunocompetent mice. In utero depletion of host HSCs increases long-term engraftment after neonatal hematopoietic cell transplantation.

Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin lymphoma characterized by the expansion of malignant CD4+ T cells in the skin. There are two main subtypes of CTCL: an indolent form termed mycosis fungoides (MF), which is largely limited to the skin, and Sezary syndrome (SS), an aggressive leukemic variant of the disease which can manifest systemically.1-3 Previous studies have demonstrated defects in cell-mediated immunity in CTCL patients, including altered cytokine profiles and impaired neutrophil function, which lead to a high incidence of recurrent bacterial and viral infections as a result of decreased Th1-mediated immunity.4-9 It has also been reported that natural killer (NK)–cell function is decreased in CTCL patients,10-14 which could contribute to an overall decrease in the innate immune response to both neoplastic cells and viral or bacterial pathogens. Previous groups have reported that NK cells from SS patients are capable of responding to activation ex vivo, indicating the potential for development of immune-based therapeutics.15 Although MF patients often have a prolonged indolent clinical course of disease that requires localized treatment, there are few effective treatments for the successful management of patients with SS. Because of the lack of success with traditional chemotherapeutic approaches, novel immune-based therapeutics are being developed for use in a multitude of hematologic diseases, including CTCL.4,16-18 Understanding the immune microenvironment in patients with CTCL will be critical to the successful design of targeted therapies for their disease. Previous studies by our group and by others have shown increased expression of interleukin-15 (IL-15) in malignant CD4+ T cells in CTCL patients.19 IL-15 acts through a trimeric IL-15R complex to enhance NK-cell maturation and function.20-22 Indeed, in a first-in-human phase 1 trial in patients with refractory solid cancer tumors, IL-15 treatment induced profound expansion of circulating NK cells ({"type":"clinical-trial","attrs":{"text":"NCT01885897","term_id":"NCT01885897"}}NCT01885897).23 Considering that IL-15 is produced by malignant cells in CTCL, we sought to study the possible effect of chronically elevated IL-15 on NK-cell function in CTCL patients. In this study, we show that NK-cell activity is significantly enhanced in CTCL, and strikingly, higher NK-cell numbers are associated with increased mortality.

Key Points S1PR1 mutations are present in 7.8% of patients with MCL and are significantly more frequent at relapse. S1PR1 mutations reduce expression of the S1PR1 receptor, which mediates migration towards the tissue-to-blood egress factor S1P in MCL.

Key Points Skeletal muscle–directed expression of FIX-Padua resulted in complete correction of HB phenotype in an inhibitor-prone dog model. Long-term immune tolerance to FIX is sustained over years upon multiple challenges with recombinant FIX protein in 2 HB models.

Key PointsSerum albumin and cholesterol levels predict survival in primary myelofibrosis, independent of each other and contemporary risk models. The cachexia index, determined by serum albumin and cholesterol levels, might further refine current prognostic models in myelofibrosis.

Key Points Graft-versus-host effects may lead to HIV-1 reactivation and cell death of infected pre-HCT CD4+ T cells. Natural killer cell activation correlates with in vitro HIV-1 transcriptional activity in the setting of HCT.

Key Points Inhibiting contact activation of factor XI during reperfusion of acute myocardial ischemia reduces infarct size in mice. Factor XII/XI contact axis inhibition may improve the outcome of coronary artery recanalization in acute myocardial infarction.

In utero hematopoietic cell transplantation (IUHCT) is a potential therapy for the treatment of numerous genetic diseases such as hemoglobinopathies, immunodeficiencies, and inborn errors of metabolism.1 In utero therapy offers the benefit of avoiding host myeloablation and immunosuppression and has been shown to be successful in multiple animal models, including mice,2-5 dogs,6,7 pigs,8,9 and sheep.10-12 The timing of IUHCT exposes the transplanted human cells to the normal fetal migratory and developmental cues that facilitate proper stem cell distribution and differentiation.11,12 Clinically, IUHCT has been successful for fetuses with severe combined immunodeficiency (SCID),13,14 but therapeutic uses for other diseases, including hemoglobinopathies, have seen limited success.15 Further investigations identified multiple barriers to successful engraftment, including lack of space within the hematopoietic niche16,17 and the maternal immune system.2,18 Among available animal models of IUHCT, the fetal mouse remains an efficient and reproducible model to study the differentiation of stem cells in a nonirradiated host. NSG (NOD-SCID IL2Rg-null) mice, which are developed with SCID and IL-2Rg-null chain mutations, are a robust platform for the engraftment of human hematopoietic cells because they have no endogenous T, B, or natural killer cells.19-22 In this study, we used IUHCT of human CD341 cells in NSG mice to create a reproducible mouse model to study stem cell engraftment, differentiation, and systemic repopulation after IUHCT.

Altered number, subset composition, and function of bone marrow innate lymphoid cells are early events in monoclonal gammopathies.Pomalidomide therapy leads to reduction in Ikzf1 and Ikzf3 and enhanced human innate lymphoid cell function in vivo.

Key Points Proteasome inhibition activates multiple kinases in myeloma cells resulting in the phosphorylation of p53, HSP27, c-JUN, and HSF1. TG02 inhibits proteasome inhibitor (PI)–induced HSF1 pS326, representing a novel mechanism for a TG02 and PI combination.

Key Points CCP-224 attenuates neutrophil-platelet aggregation in SCD patient blood. CCP-224 has the potential to prevent vaso-occlusion in SCD patients.

Key Points Fingolimod could be efficient to treat GVHD of the central nervous system. Further research should explore the use of fingolimod and other sphingosine-1-phosphate receptor agonists to prevent or treat GVHD.

Key PointsProtein S anticoagulant cofactor sensitivity and PAR1 cleavage activity were assayed for 9 recombinant APC mutants. Residues L38, K43, I73, F95, and W115 on one face of the APC light chain define an extended surface containing the protein S binding site.

Key Points RUNX1a, but not RUNX1b, is overexpressed in CD34+ cells from patients with myelodysplastic/myeloproliferative neoplasms. SRSF2P95H mutation induces RUNX1a overexpression and a monocytic phenotype in TF-1 cells.

Key Points Patients of minority race with myeloma have had less increase in population-level survival in the early 21st century than white patients. Data from clinical trials show that mortality is similar for minorities, suggesting the population-level difference is due to utilization.

Therapy-related myeloid neoplasms, such as myelodysplastic syndromes (t-MDSs) and acute myeloid leukemia (t-AML), account for 10% to 20% of all myeloid neoplasms and are recognized as a distinct subgroup according to 2008 World Health Organization (WHO) criteria.[1][1] Although t-MDS/t-AML are often

Intragenic PAX5 amplification defines a novel, relapse-prone subtype of B-cell precursor acute lymphoblastic leukemia with a poor outcome.

Key Points PARP1 is required for the maintenance of MLL-AF9 leukemias. PARP1 inhibitors enhance the therapeutic effect of cytotoxic drugs against MLL-AF9 leukemias.

Long-lived plasma cells secreting vaccinia-specific antibodies are detected in human bone marrow >35 years after the eradication of smallpox.Long-lived plasma cells secreting vaccinia-specific antibodies are still able to express the B-lymphocyte antigen CD19.

Key Points A novel heterozygous ITGB3 Leu718del shows loss of synchronization between the intracytoplasmic tail of β3 with that of αIIb. Decreased activation of αIIbβ3 accompanies enlarged platelets that contain giant granules and give a poor aggregation response.

Key Points High gene expression levels of MCT1 are associated with reduced PFS and OS in MM with lenalidomide-based maintenance therapy.Overexpression of MCT1 impairs efficacy of lenalidomide in human myeloma cells in vitro and in vivo., Biomarkers that predict response to lenalidomide maintenance therapy in patients with multiple myeloma (MM) have remained elusive. We have shown that immunomodulatory drugs (IMiDs) exert anti-MM activity via destabilization of MCT1 and CD147. In this study, cell samples of 654 patients with MM who received lenalidomide (n = 455), thalidomide (n = 98), or bortezomib (n = 101) maintenance were assessed by gene expression profiling and RNA sequencing, followed by correlation of MCT1 and CD147 expression with data for progression-free survival (PFS) and overall survival (OS). Patients with high expression levels of MCT1 showed significantly reduced PFS (31.9 months vs 48.2 months in MCT1high vs MCT1low; P = .03) and OS (75.9 months vs not reached [NR] in MCT1high vs MCT1low; P = .001) in cases with lenalidomide maintenance, whereas MCT1 expression had no significant impact on PFS or OS in cases with bortezomib maintenance. We validated the predictive role of MCT1 for IMiD-based maintenance in an independent cohort of patients who received thalidomide (OS, 83.6 months vs NR in MCT1high vs MCT1low; P = .03). Functional validation showed that MCT1 overexpression in human MM cell lines significantly reduced the efficacy of lenalidomide, whereas no change was observed with bortezomib treatment, either in vitro or in a MM xenograft model. Our findings have established MCT1 expression as a predictive marker for response to lenalidomide-based maintenance in patients with MM.