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Experimental Hematology

Jin Zhang, Malachi Griffith, Christopher A Miller, Obi L Griffith, David H Spencer, Jason R Walker, Vincent Magrini, Sean D McGrath, Amy Ly, Nichole M Helton, Maria Trissal, Daniel C Link, Ha X Dang, David E Larson, Shashikant Kulkarni, Matthew G Cordes, Catrina C Fronick, Robert S Fulton, Jeffery M Klco, Elaine R Mardis, Timothy J Ley, Richard K Wilson, Christopher A Maher
To comprehensively detect diverse and novel RNA species, we compared deep small RNA and RNA sequencing (RNA-seq) methods applied to a primary acute myeloid leukemia (AML) sample. We were able to discover previously unannotated small RNAs using deep sequencing of a library method employing broader insert size selection. We analyzed the long non-coding RNA (lncRNA) landscape in AML by comparing deep sequencing from multiple RNA-seq library construction methods for the sample we studied, then integrating RNA-seq data from 179 AML cases...
July 28, 2017: Experimental Hematology
Arzu Yalcin, Marlon Kovarbasic, Julius Wehrle, Rainer Claus, Heiko Becker, Mahmoud Abdelkarim, Verena I Gaidzik, Andrea Schmidts, Ralph Wäsch, Heike L Pahl, Konstanze Döhner, Lars Bullinger, Justus Duyster, Michael Lübbert, Björn Hackanson
DNA methylation differences between normal and cancer tissue resulting in differential expression of genes are a hallmark of acute myeloid leukemia (AML) and can provide growth advantage for malignant cells via silencing of specific genes, e.g. transcription factors. The oligodendrocyte lineage transcription factor 2 (OLIG2) was reported to be differentially methylated and associated with prognosis in AML and - as demonstrated for acute lymphoblastic leukemia and malignant glioma - may play a role in malignant transformation...
July 28, 2017: Experimental Hematology
Bruno Martino, Corrado Mammì, Claudia Labate, Silvia Rodi, Domenica Ielo, Manuela Priolo, Maurizio Postorino, Giovanni Tripepi, Francesca Ronco, Carmelo Laganà, Caterina Musolino, Marianna Greco, Giorgio La Nasa, Giovanni Caocci
Impaired fasting glucose (IFG) and type 2 diabetes (T2D) represents adverse events in Chronic Myeloid Leukemia (CML) patients treated with the second-generation tyrosine kinase inhibitor (TKI) nilotinib. A genetic risk score (uGRS) for the prediction of insulin resistance, consisting of 10 multiple single-nucleotide polymorphisms (SNPs), has been proposed. We evaluated the uGRS predictivity in 61 CML patients treated with nilotinib. Patients were genotyped for IRS1, GRB14, ARL15, PPARG, PEPD, ANKRD55/MAP3K1, PDGFC, LYPLAL1, RSPO3, and FAM13A1 genes...
July 28, 2017: Experimental Hematology
Michael C Gundry, Daniel P Dever, David Yudovich, Daniel E Bauer, Simon Haas, Adam C Wilkinson, Sofie Singbrant
The hematopoietic system is responsible for transporting oxygen and nutrients, fighting infections, and repairing tissue damage. Hematopoietic system dysfunction therefore causes a range of serious health consequences. Lifelong hematopoiesis is maintained by repopulating multipotent hematopoietic stem cells (HSCs) that replenish shorter-lived, mature blood cell types. A prokaryotic mechanism of immunity, the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 nuclease system, has recently been "repurposed" to efficiently mutate mammalian genomes in a sequence-specific manner...
July 27, 2017: Experimental Hematology
Salvador Alonso, Richard J Jones, Gabriel Ghiaur
The bone marrow niche is essential for hematopoietic stem cells to maintain lifelong blood production, by balancing their self-renewal and differentiation. Hematologic malignancies have a similar hierarchical organization to their normal counterparts, with rare populations of cancer stem cells that rely on the microenvironment to survive and propagate their differentiated malignant progenitor cells. Cancer cells alter their microenvironment to create a supportive niche where they endure chemotherapy, survive as minimal residual disease, and eventually prevail at relapse...
July 25, 2017: Experimental Hematology
Katharina Senger, Gina Marka, Karin Soller, Vadim Sakk, Maria Carolina Florian, Hartmut Geiger
Septins are a family of filament-forming GTP-binding proteins that serve as scaffolds and diffusion barriers in various cellular processes. Septin 6 is known as a fusion partner of mixed-lineage leukemia (MLL) in infant acute myeloid leukemia (AML). The occurrence of the fusion gene is associated with a reduced expression of septin 6 itself. The role of septin 6 in hematopoiesis and whether it is involved in scaffolds within hematopoietic cells is not known. Septin 6 deficient hematopoietic stem cells (HSCs) presented with an increased engraftment potential but altered lymphoid differentiation with a reduced contribution to the T cell compartment and an increased B cell contribution...
July 24, 2017: Experimental Hematology
Sara Charmsaz, Andrew M Scott, Andrew W Boyd
The use of monoclonal antibodies and molecules derived from them has achieved considerable attention and success in recent years establishing this mode of therapy as important therapeutic strategy in many cancers and in particular in hematological tumors. Monoclonal antibodies recognize cell surface antigens expressed on target cells and mediate their function through various mechanisms, such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity or by modulating the immune system. The efficacy of monoclonal antibody therapy can be improved when conjugates to a highly potent payloads including cytotoxic drugs and radiolabelled isotopes...
July 24, 2017: Experimental Hematology
Qiuping He, Suwei Gao, Junhua Lv, Wei Li, Feng Liu
No abstract text is available yet for this article.
July 18, 2017: Experimental Hematology
Ciaran Hassan, Ebrahim Afshinnekoo, Shixiu Wu, Christopher E Mason
Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy with an exceedingly poor prognosis: a 5-year overall survival rate of 40%-45% in the young and a 5-year survival rate of less than 10% in the elderly (>60 years of age). Although a high percentage of patients enters complete remission after chemotherapeutic intervention, the majority of patients relapse within 3 years. Such stark prognostic outcomes highlight the need for additional clinical research, basic discovery, and molecular delineation of the etiologies and mechanisms behind responses to therapy that lead to relapse...
July 10, 2017: Experimental Hematology
Isadora F G Sena, Pedro H D M Prazeres, Gabryella S P Santos, Isabella T Borges, Patrick O Azevedo, Julia P Andreotti, Viviani M Almeida, Ana E Paiva, Daniel A P Guerra, Luiza Lousado, Luanny Souto, Akiva Mintz, Alexander Birbrair
Bone marrow fibrosis is a critical component of primary myelofibrosis in which normal bone marrow tissue and blood-forming cells are gradually replaced with scar tissue. The specific cellular and molecular mechanisms that cause bone marrow fibrosis are not understood. A recent study using state-of-the-art techniques, including in vivo lineage tracing, provides evidence that Gli1(+) cells are the cells responsible for fibrotic disease in the bone marrow. Strikingly, genetic depletion of Gli1(+) cells rescues bone marrow failure and abolishes myelofibrosis...
July 6, 2017: Experimental Hematology
Daniel Lucas, Heather A O'Leary, Benjamin L Ebert, Chad A Cowan, Cedric S Tremblay
Since the end of the 20th century, novel approaches have emerged to manipulate experimental models of hematological disorders so that they more accurately mirror what is observed in the clinical setting. Despite these technological advances, the characterization of crucial genes for benign or malignant hematological disorders remains challenging, given the dynamic nature of the hematopoietic system and the genetic heterogeneity of these disorders. To overcome this limitation, genome-editing technologies have been developed to manipulate the genome specifically via deletion, insertion, or modification of targeted loci...
June 28, 2017: Experimental Hematology
Alison A Laing, Christine J Harrison, Brenda E S Gibson, Karen Keeshan
Acute myeloid leukemia (AML) develops when there is a block in differentiation and uncontrolled proliferation of myeloid precursors, resulting in bone marrow failure. AML is a clinically, morphologically, and genetically heterogeneous disease, and biological differences between adult and childhood AML have been identified. AML comprises 15%-20% of all children <15 years of age diagnosed with acute leukemia. Relapse occurs in up to 40% of children with AML and is the most common cause of death [1,2]. Relapse arises from leukemic stem cells (LSCs) that persist after conventional chemotherapy...
June 28, 2017: Experimental Hematology
Matilda Billing, Emma Rörby, Maria Dahl, Ulrika Blank, Silja Andradottír, Mats Ehinger, Stefan Karlsson
Transforming growth factor-β (TGFβ) is a member of a large family of polypeptide growth factors. TGFβ signals mainly through the intracellular proteins Smad2 and Smad3, which are highly similar in amino acid sequence identity. A number of studies have shown that these proteins, dependent on context, have distinct roles in the TGFβ signaling pathway. TGFβ is one of the most potent inhibitors of hematopoietic stem and progenitor cell proliferation in vitro, but its role in hematopoiesis in vivo is still being determined...
June 27, 2017: Experimental Hematology
Lai N Chan, Markus Müschen
B-lineage and myeloid leukemia cells are often transformed by the same oncogenes, but have different biological and clinical characteristics. Although B-lineage acute lymphoblastic leukemia (B-ALL) cells are characterized by a state of chronic energy deficit, myeloid leukemia cells show abundant energy reserve. Interestingly, fasting has been demonstrated to inhibit selectively the development of B-ALL but not myeloid leukemia, further suggesting that lineage identity may be linked to divergent metabolic states in hematopoietic malignancies...
June 24, 2017: Experimental Hematology
Takaomi Sanda, Wei Zhong Leong
In hematopoietic cell development, the transcriptional program is strictly regulated in a lineage- and stage-specific manner that requires a number of transcription factors to work in a cascade or in a loop, in addition to interactions with nonhematopoietic cells in the microenvironment. Disruption of the transcriptional program alters the cellular state and may predispose cells to the acquisition of genetic abnormalities. Early studies have shown that proteins that promote cell differentiation often serve as tumor suppressors, whereas inhibitors of those proteins act as oncogenes in the context of acute leukemia...
June 24, 2017: Experimental Hematology
Manoj K Pandey, Krishne Gowda, Shen-Shu Sung, Thomas Abraham, Tulin Budak-Alpdogan, Giampolo Talamo, Sinisa Dovat, Shantu Amin
Bruton's tyrosine kinase (BTK) regulates many vital signaling pathways and plays a critical role in cell proliferation, survival, migration, and resistance. Previously, we reported that a small molecule, KS99, is an inhibitor of tubulin polymerization. In the present study, we explored whether KS99 is a dual inhibitor of BTK and tubulin polymerization. Although it is known that BTK is required for clonogenic growth and resistance, and microtubules are essential for cancer cell growth, dual targeting of these two components has not been explored previously...
June 22, 2017: Experimental Hematology
Seka Lazare, Albertina Ausema, Aaffien C Reijne, Gertjan van Dijk, Ronald van Os, Gerald de Haan
Hematopoietic stem cells (HSCs) undergo a profound functional decline during normal aging. Because caloric or dietary restriction has been shown to delay multiple aspects of the aging process in many species, we explored the consequences of lifelong caloric restriction, or conversely, lifelong excess caloric intake, on HSC numbers and function. Although caloric restriction prevented age-dependent increases in bone marrow cellularity, caloric restriction was not able to prevent functional decline of aged, long-term HSC functioning...
June 16, 2017: Experimental Hematology
Ivan Sloma, Maria Teresa Mitjavila-Garcia, Olivier Feraud, Frank Griscelli, Noufissa Oudrhiri, Sanaa El Marsafy, Emilie Gobbo, Dominique Divers, Alexis Proust, David M Smadja, Christophe Desterke, Annaick Carles, Yusanna Ma, Martin Hirst, Marco A Marra, Connie J Eaves, Annelise Bennaceur-Griscelli, Ali G Turhan
We report here the first use of whole-genome sequencing (WGS) to examine the initial clonal dynamics in an unusual patient with chronic myeloid leukemia (CML), who presented in chronic phase (CP) with doubly marked BCR-ABL1(+)/JAK2(V617F)-mutant cells and, over a 9-year period, progressed into an accelerated phase (AP) and then terminal blast phase (BP). WGS revealed that the diagnostic cells also contained mutations in ASXL1, SEC23B, MAD1L1, and RREB1 as well as 12,000 additional uncommon DNA variants. WGS of endothelial cells generated from circulating precursors revealed many of these were shared with the CML clone...
June 8, 2017: Experimental Hematology
Shaina N Porter, Jeffrey A Magee
Acute myeloid leukemia (AML) cells often co-opt normal hematopoietic stem cell (HSC) programs to drive neoplastic proliferation, and HSC-related gene expression signatures have been identified as biomarkers for poor prognosis in AML patients. We sought to identify new regulators of HSCs and AML cells from previously published HSC and leukemia stem cell (LSC) gene expression signatures. We identified PRKCH (protein kinase C eta) as a gene that is highly expressed in both mouse and human HSCs, as well as in LSCs from independent cohorts of AML patients...
June 6, 2017: Experimental Hematology
Kirsten M Williams, Amber R Moore, Philip J Lucas, Juin Wang, Catherine V Bare, Ronald E Gress
Impaired immune reconstitution after hematopoietic stem cell transplantation (HSCT) is attributed in part to impaired thymopoiesis. Recent data suggest that precursor input may be a point of regulation for the thymus. We hypothesized that administration of FLT3 ligand (FLT3L) would enhance thymopoiesis after adoptive transfer of aged, FLT3L-treated bone marrow (BM) to aged, Lupron-treated hosts by increasing murine HSC (Lin([minus])Sca1(+)c-Kit(+) [LSK] cells) trafficking and survival. In murine models of aged and young hosts, we show that FLT3L enhances thymopoiesis in aged, Lupron-treated hosts through increased survival and export of LSK cells via CXCR4 regulation...
August 2017: Experimental Hematology
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