2018 WHO-EORTC classification update
(Source: Blood)
Source: Blood - April 18, 2019 Category: Hematology Tags: Free Research Articles, CME article CONTINUING MEDICAL EDUCATION (CME) QUESTIONS Source Type: research

Nankanja R, Kiyaga C, Geisberg M, Serrao E, Balyegyusa S. Implementation of a sickle cell disease screening initiative in Uganda with HemoTypeSC™ [abstract]. Blood. 2018;132(suppl 1). Abstract LBA-3.
(Source: Blood)
Source: Blood - April 18, 2019 Category: Hematology Tags: Free Research Articles RETRACTIONS Source Type: research

Cannibalistic acute myeloid leukemia with ZMYND11-MBTD1 fusion
(Source: Blood)
Source: Blood - April 18, 2019 Category: Hematology Authors: Plesa, A., Sujobert, P. Tags: Free Research Articles, BloodWork, Myeloid Neoplasia BLOOD WORK Source Type: research

Disrupted filamin A/{alpha}IIb{beta}3 interaction induces macrothrombocytopenia by increasing RhoA activity
Filamin A (FLNa) links the cell membrane with the cytoskeleton and is central in several cellular processes. Heterozygous mutations in the X-linked FLNA gene are associated with a large spectrum of conditions, including macrothrombocytopenia, called filaminopathies. Using an isogenic pluripotent stem cell model derived from patients, we show that the absence of the FLNa protein in megakaryocytes (MKs) leads to their incomplete maturation, particularly the inability to produce proplatelets. Reduction in proplatelet formation potential is associated with a defect in actomyosin contractility, which results from inappropriate ...
Source: Blood - April 18, 2019 Category: Hematology Authors: Donada, A., Balayn, N., Sliwa, D., Lordier, L., Ceglia, V., Baschieri, F., Goizet, C., Favier, R., Tosca, L., Tachdjian, G., Denis, C. V., Plo, I., Vainchenker, W., Debili, N., Rosa, J.-P., Bryckaert, M., Raslova, H. Tags: Phagocytes, Granulocytes, and Myelopoiesis PLATELETS AND THROMBOPOIESIS Source Type: research

Altered NFE2 activity predisposes to leukemic transformation and myelosarcoma with AML-specific aberrations
In acute myeloid leukemia (AML), acquired genetic aberrations carry prognostic implications and guide therapeutic decisions. Clinical algorithms have been improved by the incorporation of novel aberrations. Here, we report the presence and functional characterization of mutations in the transcription factor NFE2 in patients with AML and in a patient with myelosarcoma. We previously described NFE2 mutations in patients with myeloproliferative neoplasms and demonstrated that expression of mutant NFE2 in mice causes a myeloproliferative phenotype. Now, we show that, during follow-up, 34% of these mice transform to leukemia pr...
Source: Blood - April 18, 2019 Category: Hematology Authors: Jutzi, J. S., Basu, T., Pellmann, M., Kaiser, S., Steinemann, D., Sanders, M. A., Hinai, A. S. A., Zeilemaker, A., Bojtine Kovacs, S., Koellerer, C., Ostendorp, J., Aumann, K., Wang, W., Raffoux, E., Cassinat, B., Bullinger, L., Schlegelberger, B., Valk, Tags: Myeloid Neoplasia Source Type: research

Serum levels of TARC, MDC, IL-10, and soluble CD163 in Hodgkin lymphoma: a SWOG S0816 correlative study
Serum soluble chemokines/cytokines produced by Hodgkin cells and the tumor microenvironment might be of value as biomarkers in classic Hodgkin lymphoma (cHL). We assessed serum thymus and activation-related chemokine (TARC), macrophage-derived chemokine (MDC), interleukin-10 (IL-10), and soluble CD163 (sCD163) levels at baseline, time of interim fluorodeoxyglucose positron emission tomography (PET), and after therapy in cHL patients treated on S0816, an intergroup phase 2 response-adapted study evaluating escalated therapy for interim PET (PET2)–positive patients (www.clinicaltrials.gov #NCT00822120). Epstein-Barr vi...
Source: Blood - April 18, 2019 Category: Hematology Authors: Hsi, E. D., Li, H., Nixon, A. B., Schöder, H., Bartlett, N. L., LeBlanc, M., Smith, S., Kahl, B. S., Leonard, J. P., Evens, A. M., Scott, D. W., Rimsza, L. M., Friedberg, J. W. Tags: Lymphoid Neoplasia, Brief Reports, Clinical Trials and Observations Source Type: research

Viral, immunologic, and clinical features of primary effusion lymphoma
Primary effusion lymphoma (PEL) is an aggressive HIV-associated lymphoma with a relatively poor prognosis in the era of effective HIV therapy. Kaposi sarcoma herpesvirus (KSHV) is the etiologic agent, and ~80% of tumors are coinfected with Epstein-Barr virus (EBV). A better understanding of how KSHV-related immune dysregulation contributes to the natural history of PEL will improve outcomes. Twenty patients with PEL diagnosed between 2000 and 2013, including 19 treated with modified infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone (EPOCH), were identified. We compared their clinical, ...
Source: Blood - April 18, 2019 Category: Hematology Authors: Lurain, K., Polizzotto, M. N., Aleman, K., Bhutani, M., Wyvill, K. M., Goncalves, P. H., Ramaswami, R., Marshall, V. A., Miley, W., Steinberg, S. M., Little, R. F., Wilson, W., Filie, A. C., Pittaluga, S., Jaffe, E. S., Whitby, D., Yarchoan, R., Uldrick, Tags: Lymphoid Neoplasia, Clinical Trials and Observations Source Type: research

Parsaclisib, a potent and highly selective PI3K{delta} inhibitor, in patients with relapsed or refractory B-cell malignancies
This phase 1/2 study assessed parsaclisib (INCB050465), a next-generation, potent, and highly selective phosphatidylinositol 3-kinase (PI3K) inhibitor, in patients with relapsed or refractory B-cell malignancies, alone or in combination with a Janus kinase 1 inhibitor (itacitinib) or chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide). Seventy-two patients received parsaclisib monotherapy (5-45 mg once daily). Expansion doses were 20 and 30 mg once daily; intermittent dosing at 20 mg (once daily for 9 weeks, then once weekly) was explored. No dose-limiting toxicities were identified, and maximum tolerated dose...
Source: Blood - April 18, 2019 Category: Hematology Authors: Forero-Torres, A., Ramchandren, R., Yacoub, A., Wertheim, M. S., Edenfield, W. J., Caimi, P., Gutierrez, M., Akard, L., Escobar, C., Call, J., Persky, D., Iyer, S., DeMarini, D. J., Zhou, L., Chen, X., Dawkins, F., Phillips, T. J. Tags: Lymphoid Neoplasia Source Type: research

PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia
We report here that Phf6 deletion in mice resulted in a reduced number of hematopoietic stem cells (HSCs), an increased number of hematopoietic progenitor cells, and an increased proportion of cycling stem and progenitor cells. Loss of PHF6 caused increased and sustained hematopoietic reconstitution in serial transplantation experiments. Interferon-stimulated gene expression was upregulated in the absence of PHF6 in hematopoietic stem and progenitor cells. The numbers of hematopoietic progenitor cells and cycling hematopoietic stem and progenitor cells were restored to normal by combined loss of PHF6 and the interferon &al...
Source: Blood - April 18, 2019 Category: Hematology Authors: McRae, H. M., Garnham, A. L., Hu, Y., Witkowski, M. T., Corbett, M. A., Dixon, M. P., May, R. E., Sheikh, B. N., Chiang, W., Kueh, A. J., Nguyen, T. A., Man, K., Gloury, R., Aubrey, B. J., Policheni, A., Di Rago, L., Alexander, W. S., Gray, D. H. D., Stra Tags: Hematopoiesis and Stem Cells Source Type: research

Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease
Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder. The anti–interleukin 6 (IL-6) therapy siltuximab is not available everywhere, and is not effective for over one-half of patients. Alternative treatment approaches are urgently needed. In the first iMCD clinical trial directed against a target other than IL-6 signaling, we investigated a thalidomide-cyclophosphamide-prednisone (TCP) regimen in newly diagnosed iMCD patients. This single-center, single-arm, phase 2 study enrolled 25 newly diagnosed iMCD patients between June 2015 and June 2018. The TCP regimen (thalidomide 100 mg da...
Source: Blood - April 18, 2019 Category: Hematology Authors: Zhang, L., Zhao, A.-l., Duan, M.-h., Li, Z.-y., Cao, X.-x., Feng, J., Zhou, D.-b., Zhong, D.-r., Fajgenbaum, D. C., Li, J. Tags: Immunobiology and Immunotherapy, Lymphoid Neoplasia, Clinical Trials and Observations Source Type: research

Taking a "BiTE out of ALL": blinatumomab approval for MRD-positive ALL
Blinatumomab, a bispecific T-cell engager (BiTE) associated with improved survival in relapsed or refractory acute lymphoblastic leukemia (ALL), was recently approved for treatment of minimal residual disease (MRD). MRD is an important predictor of survival in ALL, and recent studies suggest that achievement of MRD-negativity with blinatumomab improves outcomes in patients with ALL. However, further research is needed to determine how to optimally incorporate blinatumomab, and other novel therapies, into current therapies for ALL. (Source: Blood)
Source: Blood - April 18, 2019 Category: Hematology Authors: Curran, E., Stock, W. Tags: Immunobiology and Immunotherapy, Lymphoid Neoplasia, Blood Spotlight, Clinical Trials and Observations Source Type: research

The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas
Primary cutaneous lymphomas are a heterogeneous group of T- and B-cell lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. The 2005 World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) consensus classification has served as a golden standard for the diagnosis and classification of these conditions. In September 2018, an updated version of the WHO-EORTC was published in the fourth edition of the WHO Classification of Skin Tumours Blue Book. In this classification, primary cutaneous acral CD8+ T-cell lymphoma and Epstein-Bar...
Source: Blood - April 18, 2019 Category: Hematology Authors: Willemze, R., Cerroni, L., Kempf, W., Berti, E., Facchetti, F., Swerdlow, S. H., Jaffe, E. S. Tags: Special Reports, Free Research Articles, Lymphoid Neoplasia, CME article Source Type: research

{alpha}IIb{beta}3 changes gears in MKs and platelets
(Source: Blood)
Source: Blood - April 18, 2019 Category: Hematology Authors: Sugimoto, N., Eto, K. Tags: Free Research Articles COMMENTS Source Type: research

Context-specific tumor suppression by PHF6
(Source: Blood)
Source: Blood - April 18, 2019 Category: Hematology Authors: Trowbridge, J. J. Tags: Free Research Articles COMMENTS Source Type: research

Storming the Castle with TCP
(Source: Blood)
Source: Blood - April 18, 2019 Category: Hematology Authors: van Rhee, F., Stone, K. Tags: Free Research Articles COMMENTS Source Type: research

When nucleated RBCs "count" in the peripheral blood: a unique case of post-essential thrombocythemia myelofibrosis
(Source: Blood)
Source: Blood - April 11, 2019 Category: Hematology Authors: Thompson, M., Lynch, D. Tags: Free Research Articles, BloodWork, Myeloid Neoplasia BLOOD WORK Source Type: research

Immune dysregulation: EBV+ DLBCL and HLH in a patient with T-LGL
(Source: Blood)
Source: Blood - April 11, 2019 Category: Hematology Authors: Zhan, Y., Teruya-Feldstein, J. Tags: Free Research Articles, BloodWork, Lymphoid Neoplasia BLOOD WORK Source Type: research

Clinical responses and persistent BRAF V600E+ blood cells in children with LCH treated with MAPK pathway inhibition
(Source: Blood)
Source: Blood - April 11, 2019 Category: Hematology Authors: Eckstein, O. S., Visser, J., Rodriguez-Galindo, C., Allen, C. E., the NACHO-LIBRE Study Group Tags: Pediatric Hematology, Myeloid Neoplasia, Clinical Trials and Observations Letter to Blood Source Type: research

CDK6 coordinates JAK2V617F mutant MPN via NF-{kappa}B and apoptotic networks
We describe a critical role for CDK6 in MPN evolution. The absence of Cdk6 ameliorates clinical symptoms and prolongs survival. The CDK6 protein interferes with 3 hallmarks of disease: besides regulating malignant stem cell quiescence, it promotes nuclear factor B (NF-B) signaling and contributes to cytokine production while inhibiting apoptosis. The effects are not mirrored by palbociclib, showing that the functions of CDK6 in MPN pathogenesis are largely kinase independent. Our findings thus provide a rationale for targeting CDK6 in MPN. (Source: Blood)
Source: Blood - April 11, 2019 Category: Hematology Authors: Uras, I. Z., Maurer, B., Nivarthi, H., Jodl, P., Kollmann, K., Prchal-Murphy, M., Milosevic Feenstra, J. D., Zojer, M., Lagger, S., Grausenburger, R., Grabner, B., Holly, R., Kavirayani, A., Bock, C., Gisslinger, H., Valent, P., Kralovics, R., Sexl, V. Tags: Hematopoiesis and Stem Cells, Myeloid Neoplasia Source Type: research

Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma
Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for>50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct ...
Source: Blood - April 11, 2019 Category: Hematology Authors: Heavican, T. B., Bouska, A., Yu, J., Lone, W., Amador, C., Gong, Q., Zhang, W., Li, Y., Dave, B. J., Nairismägi, M.-L., Greiner, T. C., Vose, J., Weisenburger, D. D., Lachel, C., Wang, C., Fu, K., Stevens, J. M., Lim, S. T., Ong, C. K., Gascoyne, Tags: Lymphoid Neoplasia Source Type: research

Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy
Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease–negative (MRD-negative) complete remission (CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 ...
Source: Blood - April 11, 2019 Category: Hematology Authors: Hay, K. A., Gauthier, J., Hirayama, A. V., Voutsinas, J. M., Wu, Q., Li, D., Gooley, T. A., Cherian, S., Chen, X., Pender, B. S., Hawkins, R. M., Vakil, A., Steinmetz, R. N., Schoch, G., Chapuis, A. G., Till, B. G., Kiem, H.-P., Ramos, J. D., Shadman, M., Tags: Immunobiology and Immunotherapy, Lymphoid Neoplasia, Clinical Trials and Observations Source Type: research

Characterization and treatment of congenital thrombotic thrombocytopenic purpura
In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease. (Source: Blood)
Source: Blood - April 11, 2019 Category: Hematology Authors: Alwan, F., Vendramin, C., Liesner, R., Clark, A., Lester, W., Dutt, T., Thomas, W., Gooding, R., Biss, T., Watson, H. G., Cooper, N., Rayment, R., Cranfield, T., van Veen, J. J., Hill, Q. A., Davis, S., Motwani, J., Bhatnagar, N., Priddee, N., David, M., Tags: Thrombocytopenia, Platelets and Thrombopoiesis, Clinical Trials and Observations Source Type: research

Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet
Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion–based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvag...
Source: Blood - April 11, 2019 Category: Hematology Authors: Sanz, M. A., Fenaux, P., Tallman, M. S., Estey, E. H., Löwenberg, B., Naoe, T., Lengfelder, E., Döhner, H., Burnett, A. K., Chen, S.-J., Mathews, V., Iland, H., Rego, E., Kantarjian, H., Ades, L., Avvisati, G., Montesinos, P., Platzbecker, Tags: Special Reports, Myeloid Neoplasia, Clinical Trials and Observations Source Type: research

Vitamin D receptor-mediated skewed differentiation of macrophages initiates myelofibrosis and subsequent osteosclerosis
Myelofibrosis in myeloproliferative neoplasms (MPNs) with mutations such as JAK2V617F is an unfavorable sign for uncontrollable disease progression in the clinic and is complicated with osteosclerosis whose pathogenesis is largely unknown. Because several studies have revealed that macrophages are an indispensable supporter for bone-forming osteoblasts, we speculated that macrophages might play a significant role in the proliferation of collagen-producing myofibroblasts in marrow fibrotic tissues. Here, we show that myelofibrosis critically depends on macrophages whose differentiation is skewed by vitamin D receptor (VDR) ...
Source: Blood - April 11, 2019 Category: Hematology Authors: Wakahashi, K., Minagawa, K., Kawano, Y., Kawano, H., Suzuki, T., Ishii, S., Sada, A., Asada, N., Sato, M., Kato, S., Shide, K., Shimoda, K., Matsui, T., Katayama, Y. Tags: Plenary Papers, Myeloid Neoplasia, Phagocytes, Granulocytes, and Myelopoiesis Source Type: research

Running the tank to empty: how far can the CAR go?
(Source: Blood)
Source: Blood - April 11, 2019 Category: Hematology Authors: Vasu, S., Jaglowski, S. M. Tags: Free Research Articles COMMENTS Source Type: research

Congenital TTP: toward a turning point
(Source: Blood)
Source: Blood - April 11, 2019 Category: Hematology Authors: George, J. N. Tags: Free Research Articles COMMENTS Source Type: research

I myelofibrosis! Veni VitD! Et tu, macrophage?
(Source: Blood)
Source: Blood - April 11, 2019 Category: Hematology Authors: Ng, A. P. Tags: Free Research Articles COMMENTS Source Type: research

Contamination
(Source: Blood)
Source: Blood - April 4, 2019 Category: Hematology Authors: Bloch, J., Blum, S. Tags: Free Research Articles, BloodWork, Phagocytes, Granulocytes, and Myelopoiesis BLOOD WORK Source Type: research

Biphenotypic plasma cell myeloma
(Source: Blood)
Source: Blood - April 4, 2019 Category: Hematology Authors: Kurt, H., Ferreira, K. A. Tags: Multiple Myeloma, Free Research Articles, BloodWork, Lymphoid Neoplasia BLOOD WORK Source Type: research

Tumor mutational burden and other predictive immunotherapy markers in histiocytic neoplasms
(Source: Blood)
Source: Blood - April 4, 2019 Category: Hematology Authors: Goyal, G., Lau, D., Nagle, A. M., Vassallo, R., Rech, K. L., Ryu, J. H., Davidge-Pitts, C. J., Tobin, W. O., Koster, M. J., Bennani, N. N., Shah, M. V., Liu, M. C., Go, R. S., on behalf of the Mayo Clinic Histiocytosis Working Group Tags: Immunobiology and Immunotherapy, Myeloid Neoplasia Letter to Blood Source Type: research

Thrombotic microangiopathy as a cause of cardiovascular toxicity from the BCR-ABL1 tyrosine kinase inhibitor ponatinib
The third-generation tyrosine kinase inhibitor (TKI) ponatinib has been associated with high rates of acute ischemic events. The pathophysiology responsible for these events is unknown. We hypothesized that ponatinib produces an endothelial angiopathy involving excessive endothelial-associated von Willebrand factor (VWF) and secondary platelet adhesion. In wild-type mice and ApoE–/– mice on a Western diet, ultrasound molecular imaging of the thoracic aorta for VWF A1-domain and glycoprotein-Ibα was performed to quantify endothelial-associated VWF and platelet adhesion. After treatment of wild-type mice fo...
Source: Blood - April 4, 2019 Category: Hematology Authors: Latifi, Y., Moccetti, F., Wu, M., Xie, A., Packwood, W., Qi, Y., Ozawa, K., Shentu, W., Brown, E., Shirai, T., McCarty, O. J., Ruggeri, Z., Moslehi, J., Chen, J., Druker, B. J., Lopez, J. A., Lindner, J. R. Tags: Myeloid Neoplasia, Platelets and Thrombopoiesis, Thrombosis and Hemostasis, Vascular Biology Source Type: research

Increased galactose expression and enhanced clearance in patients with low von Willebrand factor
Glycan determinants on von Willebrand factor (VWF) play critical roles in regulating its susceptibility to proteolysis and clearance. Abnormal glycosylation has been shown to cause von Willebrand disease (VWD) in a number of different mouse models. However, because of the significant technical challenges associated with accurate assessment of VWF glycan composition, the importance of carbohydrates in human VWD pathogenesis remains largely unexplored. To address this, we developed a novel lectin-binding panel to enable human VWF glycan characterization. This methodology was then used to study glycan expression in a cohort o...
Source: Blood - April 4, 2019 Category: Hematology Authors: Aguila, S., Lavin, M., Dalton, N., Patmore, S., Chion, A., Trahan, G. D., Jones, K. L., Keenan, C., Brophy, T. M., OConnell, N. M., Ryan, K., Byrne, M., Nolan, M., Patel, A., Preston, R. J. S., James, P., Di Paola, J., OSullivan, J. M., ODonnell, J. S. Tags: Thrombosis and Hemostasis Source Type: research

Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma
Three proteasome inhibitors have garnered regulatory approvals in various multiple myeloma settings; but drug resistance is an emerging challenge, prompting interest in blocking upstream components of the ubiquitin-proteasome pathway. One such attractive target is the E1 ubiquitin-activating enzyme (UAE); we therefore evaluated the activity of TAK-243, a novel and specific UAE inhibitor. TAK-243 potently suppressed myeloma cell line growth, induced apoptosis, and activated caspases while decreasing the abundance of ubiquitin-protein conjugates. This was accompanied by stabilization of many short-lived proteins, including p...
Source: Blood - April 4, 2019 Category: Hematology Authors: Zhuang, J., Shirazi, F., Singh, R. K., Kuiatse, I., Wang, H., Lee, H. C., Berkova, Z., Berger, A., Hyer, M., Chattopadhyay, N., Syed, S., Shi, J. Q., Yu, J., Shinde, V., Tirrell, S., Jones, R. J., Wang, Z., Davis, R. E., Orlowski, R. Z. Tags: Multiple Myeloma, Lymphoid Neoplasia Source Type: research

The BRISC deubiquitinating enzyme complex limits hematopoietic stem cell expansion by regulating JAK2 K63-ubiquitination
Hematopoietic stem cell (HSC) homeostasis is controlled by cytokine receptor–mediated Janus kinase 2 (JAK2) signaling. We previously found that JAK2 is promptly ubiquitinated upon cytokine stimulation. Whether a competing JAK2 deubiquitination activity exists is unknown. LNK is an essential adaptor protein that constrains HSC expansion through dampening thrombopoietin (TPO)–induced JAK2 signaling. We show here that a LNK-associated lysine-63 (K63)–deubiquitinating enzyme complex, Brcc36 isopeptidase complex (BRISC), attenuates HSC expansion through control of JAK2 signaling. We pinpoint a direct interacti...
Source: Blood - April 4, 2019 Category: Hematology Authors: Donaghy, R., Han, X., Rozenova, K., Lv, K., Jiang, Q., Doepner, M., Greenberg, R. A., Tong, W. Tags: Hematopoiesis and Stem Cells Source Type: research

A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403
Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children’s Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for respo...
Source: Blood - April 4, 2019 Category: Hematology Authors: Stock, W., Luger, S. M., Advani, A. S., Yin, J., Harvey, R. C., Mullighan, C. G., Willman, C. L., Fulton, N., Laumann, K. M., Malnassy, G., Paietta, E., Parker, E., Geyer, S., Mrozek, K., Bloomfield, C. D., Sanford, B., Marcucci, G., Liedtke, M., Claxton, Tags: Pediatric Hematology, Lymphoid Neoplasia, Clinical Trials and Observations Source Type: research

How I treat early-relapsing follicular lymphoma
Follicular lymphoma (FL) is the most frequently occurring indolent non-Hodgkin lymphoma, with generally favorable outcomes but a variable clinical course. Recent studies have elucidated the consistent and reproducible frequency of early disease progression in FL, occurring in ~20% of patients. Relapse of FL within 24 months of chemoimmunotherapy (POD24) is now established as a robust marker of poor survival, leading to increased risk of death. Currently, there is no established method of identifying patients at risk for early disease progression at the time of their FL diagnosis. However, numerous studies worldwide are inv...
Source: Blood - April 4, 2019 Category: Hematology Authors: Casulo, C., Barr, P. M. Tags: How I Treat, Free Research Articles, Lymphoid Neoplasia, Clinical Trials and Observations Source Type: research

Myeloma bone disease: from biology findings to treatment approaches
Bone disease is a cardinal complication of multiple myeloma that affects quality of life and survival. Osteocytes have emerged as key players in the development of myeloma-related bone disease. Along with other factors, they participate in increased osteoclast activity, decreased osteoblast function, and immunosuppressed marrow microenvironment, which deregulate bone turnover and result in bone loss and skeletal-related events. Denosumab is a novel alternative to bisphosphonates against myeloma bone disease. Special considerations in this constantly evolving field are thoroughly discussed. (Source: Blood)
Source: Blood - April 4, 2019 Category: Hematology Authors: Terpos, E., Ntanasis-Stathopoulos, I., Dimopoulos, M. A. Tags: Multiple Myeloma, Lymphoid Neoplasia, Blood Spotlight, Clinical Trials and Observations Source Type: research

The von Willebrand factor D'D3 assembly and structural principles for factor VIII binding and concatemer biogenesis
D assemblies make up half of the von Willebrand factor (VWF), yet are of unknown structure. D1 and D2 in the prodomain and D'D3 in mature VWF at Golgi pH form helical VWF tubules in Weibel Palade bodies and template dimerization of D3 through disulfides to form ultralong VWF concatemers. D'D3 forms the binding site for factor VIII. The crystal structure of monomeric D'D3 with cysteine residues required for dimerization mutated to alanine was determined at an endoplasmic reticulum (ER)-like pH. The smaller C8-3, TIL3 (trypsin inhibitor-like 3), and E3 modules pack through specific interfaces as they wind around the larger, ...
Source: Blood - April 4, 2019 Category: Hematology Authors: Dong, X., Leksa, N. C., Chhabra, E. S., Arndt, J. W., Lu, Q., Knockenhauer, K. E., Peters, R. T., Springer, T. A. Tags: Plenary Papers, Thrombosis and Hemostasis Source Type: research

Ponatinib and platelets a conflict in CML
(Source: Blood)
Source: Blood - April 4, 2019 Category: Hematology Authors: Guilhot, F. Tags: Free Research Articles COMMENTS Source Type: research

Should young adults with ALL be treated as children?
(Source: Blood)
Source: Blood - April 4, 2019 Category: Hematology Authors: Dombret, H., Boissel, N. Tags: Free Research Articles COMMENTS Source Type: research

Acanthocytosis causing chronic hemolysis in a patient with advanced cirrhosis
(Source: Blood)
Source: Blood - March 28, 2019 Category: Hematology Authors: Marks, E. I., Ollila, T. A. Tags: Free Research Articles, BloodWork, Red Cells, Iron, and Erythropoiesis BLOOD WORK Source Type: research

CAR T cells mimicking an aggressive lymphoma
(Source: Blood)
Source: Blood - March 28, 2019 Category: Hematology Authors: Song, J. Y., Herrera, A. F. Tags: Immunobiology and Immunotherapy, Free Research Articles, BloodWork, Lymphoid Neoplasia BLOOD WORK Source Type: research

MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans
A large unmet medical need exists for safer antithrombotic drugs because all currently approved anticoagulant agents interfere with hemostasis, leading to an increased risk of bleeding. Genetic and pharmacologic evidence in humans and animals suggests that reducing factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with a minimal risk of bleeding. We generated a fully human antibody (MAA868) that binds the catalytic domain of both FXI (zymogen) and activated FXI. Our structural studies show that MAA868 traps FXI and activated FXI in an inactive, zymogen-like conformation, explaining its eq...
Source: Blood - March 28, 2019 Category: Hematology Authors: Koch, A. W., Schiering, N., Melkko, S., Ewert, S., Salter, J., Zhang, Y., McCormack, P., Yu, J., Huang, X., Chiu, Y.-H., Chen, Z., Schleeger, S., Horny, G., DiPetrillo, K., Muller, L., Hein, A., Villard, F., Scharenberg, M., Ramage, P., Hassiepen, U., Cot Tags: Thrombosis and Hemostasis Source Type: research

FLT3-ITD impedes retinoic acid, but not arsenic, responses in murine acute promyelocytic leukemias
Acute promyelocytic leukemia (APL) is often associated with activating FLT3 signaling mutations. These are highly related to hyperleukocytosis, a major adverse risk factor with chemotherapy-based regimens. APL is a model for oncogene-targeted therapies: all-trans retinoic acid (ATRA) and arsenic both target and degrade its ProMyelocytic Leukemia/Retinoic Acid Receptor α (PML/RARA) driver. The combined ATRA/arsenic regimen now cures virtually all patients with standard-risk APL. Although FLT3-internal tandem duplication (ITD) was an adverse risk factor for historical ATRA/chemotherapy regimens, the molecular bases for...
Source: Blood - March 28, 2019 Category: Hematology Authors: Esnault, C., Rahme, R., Rice, K. L., Berthier, C., Gaillard, C., Quentin, S., Maubert, A.-L., Kogan, S., de The, H. Tags: Myeloid Neoplasia Source Type: research

Autocrine LTA signaling drives NF-{kappa}B and JAK-STAT activity and myeloid gene expression in Hodgkin lymphoma
Persistent NF-B activation is a hallmark of the malignant Hodgkin/Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL). Genomic lesions, Epstein-Barr virus infection, soluble factors, and tumor–microenvironment interactions contribute to this activation. Here, in an unbiased approach to identify the cHL cell-secreted key factors for NF-B activation, we have dissected the secretome of cultured cHL cells by chromatography and subsequent mass spectrometry. We identified lymphotoxin-α (LTA) as the causative factor for autocrine and paracrine activation of canonical and noncanonical NF-B in cHL cell lines....
Source: Blood - March 28, 2019 Category: Hematology Authors: von Hoff, L., Kärgel, E., Franke, V., McShane, E., Schulz-Beiss, K. W., Patone, G., Schleussner, N., Kolesnichenko, M., Hübner, N., Daumke, O., Selbach, M., Akalin, A., Mathas, S., Scheidereit, C. Tags: Lymphoid Neoplasia, Brief Reports Source Type: research

The HLA-B -21 dimorphism impacts on NK cell education and clinical outcome of immunotherapy in acute myeloid leukemia
Natural killer (NK) cell function is regulated by inhibitory receptors, such as the family of killer immunoglobulin-like receptors (KIRs) and the NKG2A/CD94 heterodimer. These receptors recognize cognate HLA class I molecules on potential target cells, and recent studies imply that an HLA-B dimorphism at position –21 in the gene segment encoding the leader peptide dictates whether NK cell regulation primarily relies on the KIRs or the NKG2A/CD94 receptor. The impact of this HLA-B dimorphism on NK cell–mediated destruction of leukemic cells or on the course of leukemia is largely unknown. In a first part of this...
Source: Blood - March 28, 2019 Category: Hematology Authors: Hallner, A., Bernson, E., Hussein, B. A., Ewald Sander, F., Brune, M., Aurelius, J., Martner, A., Hellstrand, K., Thoren, F. B. Tags: Immunobiology and Immunotherapy, Myeloid Neoplasia Source Type: research

Endothelial protein C receptor supports hematopoietic stem cell engraftment and expansion in Mpl-deficient mice
Thrombopoietin (Thpo)/myeloproliferative leukemia virus oncogene (Mpl) signaling controls hematopoietic stem cell (HSC) self-renewal and quiescence; however, how these 2 seemingly opposing functions are controlled is not well understood. By transplantation of lentiviral-transduced hematopoietic cells in the Mpl-deficient mouse model, we addressed whether known or predicted Thpo target genes were able to rescue the Mpl-deficient phenotype of the mice. Among the tested genes, we identified endothelial protein C receptor (Epcr) to expand HSCs with the long-term (LT)-HSC surface phenotype in Mpl–/– mice and to enab...
Source: Blood - March 28, 2019 Category: Hematology Authors: Kohlscheen, S., Schenk, F., Rommel, M. G. E., Cullmann, K., Modlich, U. Tags: Hematopoiesis and Stem Cells, Transplantation Source Type: research

Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients
The prevention of relapse is the major therapeutic challenge in older patients with acute myeloid leukemia (AML) who have obtained a complete remission (CR) on intensive chemotherapy. In this randomized phase 3 study (HOVON97) in older patients (≥60 years) with AML or myelodysplastic syndrome with refractory anemia with excess of blasts, in CR/CR with incomplete hematologic recovery (CRi) after at least 2 cycles of intensive chemotherapy, we assessed the value of azacitidine as postremission therapy with respect to disease-free survival (DFS; primary end point) and overall survival (OS; secondary end point). In total, 1...
Source: Blood - March 28, 2019 Category: Hematology Authors: Huls, G., Chitu, D. A., Havelange, V., Jongen-Lavrencic, M., van de Loosdrecht, A. A., Biemond, B. J., Sinnige, H., Hodossy, B., Graux, C., Kooy, R. v. M., de Weerdt, O., Breems, D., Klein, S., Kuball, J., Deeren, D., Terpstra, W., Vekemans, M.-C., Ossenk Tags: Myeloid Neoplasia, Clinical Trials and Observations Source Type: research

Dissecting CLL through high-dimensional single-cell technologies
We now have the potential to undertake detailed analysis of the inner workings of thousands of cancer cells, one cell at a time, through the emergence of a range of techniques that probe the genome, transcriptome, and proteome combined with the development of bioinformatics pipelines that enable their interpretation. This provides an unprecedented opportunity to better understand the heterogeneity of chronic lymphocytic leukemia and how mutations, activation states, and protein expression at the single-cell level have an impact on disease course, response to treatment, and outcomes. Herein, we review the emerging applicati...
Source: Blood - March 28, 2019 Category: Hematology Authors: Gohil, S. H., Wu, C. J. Tags: Lymphoid Neoplasia, Review Articles, Review Series Source Type: research

Clonal approaches to understanding the impact of mutations on hematologic disease development
Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in di...
Source: Blood - March 28, 2019 Category: Hematology Authors: Nangalia, J., Mitchell, E., Green, A. R. Tags: Hematopoiesis and Stem Cells, Myeloid Neoplasia, Review Articles, Review Series Source Type: research