Arterial Identity Of Hemogenic Endothelium: A Key To Unlock Definitive Hematopoietic Commitment In hPSC Cultures
Derivation of human embryonic stem cells (hESCs) 20 years ago [1] followed by advances in cellular reprogramming to generate human induced pluripotent stem cells (hiPSCs) [2-5] have created alternative platforms for producing blood cells for transfusion, immunotherapies and transplantation. Although the feasibility of generating myeloid, T lymphoid, and engraftable blood cells from human pluripotent stem cells (hPSCs) has been demonstrated [6-14], scalable production of definitive hematopoietic cells, including adult-type red blood cells, megakaryocytes, T cells, and hematopoietic stem cells (HSCs) with robust multilineage...
Source: Experimental Hematology - November 27, 2018 Category: Hematology Authors: Igor I. Slukvin, Gene I. Uenishi Source Type: research

Modeling myeloid malignancies with patient-derived iPSCs
The derivation of human induced pluripotent stem cells (iPSCs) in 2007 ushered in a new era in the modeling of human diseases, including those affecting the hematopoietic system [1-3]. Significant advances over the past decade have enabled investigators to increasingly incorporate iPSC models in their research. iPSCs can empower diverse research studies, ranging from investigations into basic disease mechanisms to more translational applications, such as therapeutic target discovery, drug testing, compound screening, toxicity testing and generation of cells for transplantation [2,4]. (Source: Experimental Hematology)
Source: Experimental Hematology - November 24, 2018 Category: Hematology Authors: Eirini P. Papapetrou Source Type: research

A Track of the Clones: New developments in cellular barcoding
Methods to unambiguously mark individual cells and follow their clonal progeny over extended periods of time can provide unprecedented insights into the organizational principles operative in tissue homeostasis and regeneration. The potential of clonal tracking was initially demonstrated by studies of glucose-6-phosphate dehydrogenase (G-6-PD) cellular mosaicism [1,2]. More recently, viral integration site analysis (IS) [3-5] and integration of unique genetic “barcode” sequences [6-9] have been complemented by inducible transposon systems [10,11] and the recombination of multiple segments separated by loxP site...
Source: Experimental Hematology - November 15, 2018 Category: Hematology Authors: Anne-Marie Lyne, David G Kent, Elisa Laurenti, Kerstin Cornils, Ingmar Glauche, Leila Peri é Source Type: research

Message from the Editor
In this issue, we have stunning contributions from each of this year's International Society for Experimental Hematology (ISEH) award winners –Nancy Speck – the 2018 Don Metcalf Awardee, Atsushi Iwama – the 2018 McCulloch and Till Awardee, and Keisuke Ito – recipient of the New Investigator Presentation Award. All three made exciting presentations at the 47th Annual Scientific Meeting held August 23-26 in Los Angeles, CA this year , and all three agreed to extend their talks as peer-reviewed submissions to Experimental Hematology. (Source: Experimental Hematology)
Source: Experimental Hematology - November 12, 2018 Category: Hematology Authors: Connie Eaves Source Type: research

The case for plerixafor to replace filgrastim as the optimal agent to mobilize peripheral blood donors for allogeneic hematopoietic cell transplantation
Currently, the predominant approach to accessioning donor cells for hematopoietic cell transplantation (HCT) is the use of granulocyte colony-stimulating factor (G-CSF) treatment of the donor for a number of days, followed by leukapheresis of peripheral blood progenitor cells (G-PBs) [1]. Over 70% of adult allogeneic HCT procedures utilize G-PBs in the United States and Canada [2]. Studies have shown that allogeneic transplantation with unstimulated bone marrow (BM) allograft results in lower rates of acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) and improved quality of life compared with G-PB...
Source: Experimental Hematology - November 11, 2018 Category: Hematology Authors: Stephen Couban, Peggy C. Wong, Kirk R. Schultz Source Type: research

“The case for Plerixafor to replace Filgrastim as the optimal agent to mobilize peripheral blood donors for allogeneic hematopoietic cell transplantation”
Currently, the predominant approach to accessioning donor cells for hematopoietic cell transplantation (HCT) is the use of G-CSF treatment of the donor for a number of days followed by leukapheresis of peripheral blood progenitor cells (G-PB) [1]. Over 70% of adult allogeneic HCT utilize G-PB in the US and Canada [2]. Studies have shown that allogeneic transplantation with unstimulated bone marrow (BM) allograft results in lower rates of acute and chronic graft-versus-host disease (aGVHD and cGVHD) and improved quality of life when compared to G-PB graft [1-3]. (Source: Experimental Hematology)
Source: Experimental Hematology - November 11, 2018 Category: Hematology Authors: Stephen Couban, Peggy C. Wong, Kirk R. Schultz Source Type: research

Deferasirox selectively induces cell death in the clinically relevant population of leukemic CD34+CD38 − cells through iron chelation, induction of ROS and inhibition of HIF1α expression
Acute myelogenous leukemia (AML) is a clonal malignancy that is thought to be initiated at a stage as early as hematopoietic stem/progenitor cells [1]. The cure rates are less than 10% for older AML patients and median survival less than 1 year for these patients [2]. Although 70 –80% of younger patients achieve complete remission, most will eventually relapse and overall survival is only 40–50% at 5 years [3-4]. Drug resistance and relapse are major causes for treatment failure. Current treatments for AML such as nucleoside analogs (eg, cytosine arabinoside [ARA-C]) and anthracyclines [eg, idarubicin, daunorub...
Source: Experimental Hematology - November 8, 2018 Category: Hematology Authors: Saar Shapira, Pia Raanani, Aladin Samara, Arnon Nagler, Ido Lubin, Nadir Arber, Galit Granot Source Type: research

Modeling human RNA spliceosome mutations in the mouse: not all mice were created equal
Myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and related disorders are a heterogeneous class of blood cancers leading to ineffective hematopoiesis in the bone marrow (BM) [1,2]. Approximately 30% of MDS patients progress to acute leukemia. Median survival ranges from 97 months for low-risk categories down to 11 months for high-risk MDS [2]. The incidence of MDS in the general population is approximately four to five per 100,000 people, but this increases with age [1]. (Source: Experimental Hematology)
Source: Experimental Hematology - November 6, 2018 Category: Hematology Authors: Jane Jialu Xu, Monique F. Smeets, Shuh Ying Tan, Meaghan Wall, Louise E. Purton, Carl R. Walkley Source Type: research

MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease
Sickle cell disease (SCD) is a genetic disorder caused by the βS-globin mutation leading to production of hemoglobin S, polymer formation under low oxygen conditions, and red blood cell sickling. The net outcome of this process is chronic hemolysis, oxidative stress, anemia, and vaso-occlusive episodes of pain and organ damage. The most effective treatment fo r SCD is fetal hemoglobin (HbF; α2γ2) induction, which inhibits sickle hemoglobin polymerization through the formation of hybrid molecules [1]. (Source: Experimental Hematology)
Source: Experimental Hematology - November 6, 2018 Category: Hematology Authors: Biaoru Li, Xingguo Zhu, Christina M. Ward, Athena Starlard-Davenport, Mayuko Takezaki, Amber Berry, Alexander Ward, Caroline Wilder, Cindy Neunert, Abdullah Kutlar, Betty S. Pace Source Type: research

Modeling human RNA spliceosome mutations in the mouse: not all mice were created equal.
Myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and related disorders are a heterogeneous class of blood cancers leading to ineffective hematopoiesis in the bone marrow (BM) [1, 2]. Approximately 30% of MDS patients progress to acute leukemia. Median survival ranges from 97 months for low risk categories, down to 11 months for high risk MDS [2]. The incidence of MDS in the general population is ∼4-5 per 100,000 people, but this increases with age [1]. Population based studies in both Australia and the USA indicate a significant underestimation of the true burden of MDS, with freq...
Source: Experimental Hematology - November 6, 2018 Category: Hematology Authors: Jane Jialu Xu, Monique F Smeets, Shuh Ying Tan, Meaghan Wall, Louise E. Purton, Carl R Walkley Tags: Review Source Type: research

MIR-144 Mediated NRF2 Gene Silencing Inhibits Fetal Hemoglobin Expression in Sickle Cell Disease
Inherited genetic modifiers and pharmacologic agents that enhance fetal hemoglobin (HbF) expression reverse the clinical severity of sickle cell disease (SCD). Recent efforts to develop novel strategies of HbF induction include discovery of molecular targets that regulate γ-globin gene transcription and translation. The purpose of this study was to perform genome-wide microRNA (miRNA) analysis identify genes associated with HbF expression in patients with SCD. We isolated RNA from purified reticulocytes for microarray-based miRNA expression profiling. (Source: Experimental Hematology)
Source: Experimental Hematology - November 6, 2018 Category: Hematology Authors: Biaoru Li, Xingguo Zhu, Christina M. Ward, Athena Starlard-Davenport, Mayuko Takezaki, Amber Berry, Alexander Ward, Caroline Wilder, Cindy Neunert, Abdullah Kutlar, Betty S. Pace Source Type: research

CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p –XIAP axis
Acute myeloid leukemia (AML) is one of the most common hematological malignancies [1,2]. Despite the application of new molecular targeted drugs and progress of allogeneic hematopoietic stem cell transplantation, chemoradiotherapy is still the mainstay for the treatment of AML. However, AML cells are demonstrated to unavoidably develop primary or secondary chemoresistance, thereby resulting in refractory and recurrent disease in patients. So far, most clinical trials of chemotherapy have shown very limited benefits for refractory and recurrent AML [3]. (Source: Experimental Hematology)
Source: Experimental Hematology - November 2, 2018 Category: Hematology Authors: Jin Shang, Wei-Min Chen, Zhi-Hong Wang, Tian-Nan Wei, Zhi-Zhong Chen, Wen-Bing Wu Source Type: research

CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis
Acute myeloid leukemia (AML) is one of the most common hematological malignancies [1,2]. Despite the application of new molecular targeted drugs and progress of allogeneic hematopoietic stem cell transplantation, chemoradiotherapy is still the mainstay for the treatment of AML. However, AML cells are demonstrated to unavoidably develop primary or secondary chemo-resistance, thereby resulting in refractory and recurrent disease in patients. So far, most clinical trials of chemotherapy showed very limited benefits for refractory and recurrent AML [3]. (Source: Experimental Hematology)
Source: Experimental Hematology - November 2, 2018 Category: Hematology Authors: Jin Shang, Wei-Min Chen, Zhi-Hong Wang, Tian-Nan Wei, Zhi-Zhong Chen, Wen-Bing Wu Source Type: research

Membrane-potential compensation reveals mitochondrial volume expansion during HSC commitment
Hematopoietic stem cells (HSCs) are normally quiescent in the bone marrow, and for their ATP needs rely predominantly on glycolysis rather than the mitochondrial tricarboxylic acid (TCA) cycle [1-6]. Therefore, mitochondrial volume was widely believed to be low in HSCs, unlike multipotent progenitor (MPP) cells, which have more respirating mitochondria with higher volumes [7-9]. Mitochondria are negatively charged, due to activity of electron transport chain (ETC) that generates a proton gradient across the mitochondrial membrane. (Source: Experimental Hematology)
Source: Experimental Hematology - November 2, 2018 Category: Hematology Authors: Massimo Bonora, Kyoko Ito, Claudia Morganti, Paolo Pinton, Keisuke Ito Source Type: research

RUNX1 and the endothelial origin of blood
An account of the developmental origin of blood cannot be told without the major protagonist of the story, RUNX1. RUNX was first discovered in the fly, in the classic screen conducted by Nusslein-Volhard and Wieschaus to identify mutations that affect development [1]. The mutation runt was named for the fact that it resulted in runted embryos - a defect caused by pre-segmentation patterning defects. The runt gene was cloned by Gergen and colleagues, and the protein it encoded shown to be nuclear, but its identity as a transcription factor was not discovered at that time [2]. (Source: Experimental Hematology)
Source: Experimental Hematology - November 1, 2018 Category: Hematology Authors: Long Gao, Joanna Tober, Peng Gao, Changya Chen, Qin Zhu, Kai Tan, Nancy A. Speck Tags: Perspective Source Type: research

Emerging role of noncanonical polycomb repressive complexes in normal and malignant hematopoiesis
Polycomb group (PcG) proteins comprise the multiprotein complexes called polycomb repressive complexes (PRCs), which play an important role in the transcriptional repression of target genes through histone modifications. Two major complexes have been extensively characterized: PRC1 and PRC2, which add monoubiquitination at lysine 119 of histone H2A (H2AK119ub1) and mono-, di-, and trimethylation at lysine 27 of histone H3 (H3K27me1/me2/me3), respectively [1] (Figure 1). PRC2 is recruited to nonmethylated CpG islands (CGIs) through a not yet fully understood mechanism. (Source: Experimental Hematology)
Source: Experimental Hematology - October 26, 2018 Category: Hematology Authors: Yusuke Isshiki, Atsushi Iwama Tags: Perspective Source Type: research

Emerging role of non-canonical polycomb repressive complexes in normal and malignant hematopoiesis
Polycomb group (PcG) proteins comprise the multiprotein complexes, polycomb repressive complexes (PRCs), which play an important role in the transcriptional repression of target genes through histone modifications. Two major complexes have been extensively characterized: PRC1 and PRC2, which add mono-ubiquitination at lysine 119 of histone H2A (H2AK119ub1) and mono-, di-, and tri-methylation at lysine 27 of histone H3 (H3K27me1/me2/me3), respectively [1] (Figure 1). PRC2 is recruited to non-methylated CpG islands (CGIs) through a not yet fully understood mechanism. (Source: Experimental Hematology)
Source: Experimental Hematology - October 26, 2018 Category: Hematology Authors: Yusuke Isshiki, Atsushi Iwama Tags: Perspective Source Type: research

Effect of circadian variation on neutrophil mobilization to the peripheral blood in benign constitutional neutropenia
Benign constitutional neutropenia (BCN) — also known as benign ethnic neutropenia (BEN) — is characterized by chronic neutropenia in non-Caucasian individuals who are apparently healthy and do not have a history of recurrent infections [1-3]. (Source: Experimental Hematology)
Source: Experimental Hematology - October 24, 2018 Category: Hematology Authors: Jo ão Tadeu Damian Souto Filho, Rodrigo Doyle Portugal, Marcio Nucci Tags: Brief Communication Source Type: research

Cover 2: Editorial Board
(Source: Experimental Hematology)
Source: Experimental Hematology - October 20, 2018 Category: Hematology Source Type: research

Characterization of inv(3) cell line OCI-AML-20 with stroma-dependent CD34 expression
Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by the abnormal proliferation and differentiation of hematopoietic stem cells. Patients diagnosed with AML often have a poor prognosis, with long-term survival being affected by subtype of disease, therapy given, and ability to tolerate treatment [1]. An important classifier of the disease that can predict response to therapy and outcome is the presence of recurrent cytogenetic abnormalities. Patients with recurrent 3q mutations such as inv(3)(q21q26.2) or t(3;3)(q21;q26.2) represent a subgroup of AML with a very poor prognosis due to the high rates of ...
Source: Experimental Hematology - October 20, 2018 Category: Hematology Authors: Genna M. Luciani, Lihua Xie, David Dilworth, Anne Tierens, Yoni Moskovitz, Alex Murison, Magdalena M. Szewczyk, Amanda Mitchell, Mathieu Lupien, Liran Shlush, John E. Dick, Cheryl H. Arrowsmith, Dalia Barsyte-Lovejoy, Mark D. Minden Source Type: research

Characterization of inv(3) cell line OCI-AML-20 with stroma dependent CD34 expression
Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by the abnormal proliferation and differentiation of hematopoietic stem cells. Patients diagnosed with AML often have a poor prognosis, with long term survival being affected by subtype of disease, therapy given, and ability to tolerate treatment [1]. An important classifier of the disease that can predict response to therapy and outcome is the presence of recurrent cytogenetic abnormalities. Patients with recurrent 3q mutations such as inv(3)(q21q26.2) or t(3;3)(q21;q26.2) represent a subgroup of AML with a very poor prognosis due to the high rates of ...
Source: Experimental Hematology - October 20, 2018 Category: Hematology Authors: Genna M. Luciani, Lihua Xie, David Dilworth, Anne Tierens, Yoni Moskovitz, Alex Murison, Magdalena M. Szewczyk, Amanda Mitchell, Mathieu Lupien, Liran Shlush, John E. Dick, Cheryl H. Arrowsmith, Dalia Barsyte-Lovejoy, Mark D. Minden Source Type: research

Loss of EfnB1 in the osteogenic lineage compromises their capacity to support hematopoietic stem/progenitor cell maintenance
The hematopoietic stem/progenitor cell (HSPC) niche is composed of diverse cellular components that contribute to HSPC maintenance and niche function within the bone marrow. These include arterioles, sinusoidal endothelial cells, Nestin+ mesenchymal stem cells, stromal populations including bone marrow stromal stem cells/perivascular reticular cells, and cells of the osteogenic lineage [1 –9]. These cells are key mediators of hematopoietic stem cell (HSC) maintenance, proliferation, differentiation, and maturation, acting in a non-cell-autonomous manner through membrane-dependent or soluble chemokines and growth fact...
Source: Experimental Hematology - October 13, 2018 Category: Hematology Authors: Agnieszka Arthur, Thao M. Nguyen, Sharon Paton, Andrew C.W. Zannettino, Stan Gronthos Source Type: research

Loss of EfnB1 in the osteogenic lineage compromises their capacity to support haematopoietic stem/ progenitor cell maintenance
The haematopoietic stem/ progenitor cell (HSPC) niche is composed of diverse cellular components that contribute to HSPC maintenance and niche function within the bone marrow. These include arterioles, sinusoidal endothelial cells, Nestin+ mesenchymal stem cells, stromal populations including bone marrow stromal stem cells (BMSC)/ perivascular reticular cells and cells of the osteogenic lineage [1 –9]. These cells are key mediators of HSC maintenance, proliferation, differentiation and maturation, acting in a non-cell-autonomous manner through membrane dependent or soluble chemokines and growth factors. (Source: Experimental Hematology)
Source: Experimental Hematology - October 13, 2018 Category: Hematology Authors: Agnieszka Arthur, Thao M. Nguyen, Sharon Paton, Andrew C.W. Zannettino, Stan Gronthos Source Type: research

Establishment and characterization of immortalized erythroid progenitor cell lines derived from a common cell source
Recently, attempts have been made to produce large quantities of red blood cells (RBCs) in vitro using cell culture techniques [1-5] Although hematopoietic stem/progenitor cells or pluripotent stem cells have been considered primary candidates for in vitro RBC production, as they possess excellent characteristics for this technology [6-11], we have successfully established immortalized erythroid progenitor cell lines (imERYPCs) that can differentiate into enucleated RBCs [12]. The main advantage of these cell lines is that they can proliferate indefinitely, rapidly produce enucleated RBCs, and can be handled with ease. (So...
Source: Experimental Hematology - October 13, 2018 Category: Hematology Authors: Ryo Kurita, Koji Funato, Takaaki Abe, Yoshihisa Watanabe, Masayuki Shiba, Kenji Tadokoro, Yukio Nakamura, Tadashi Nagai, Masahiro Satake Tags: Brief Communication Source Type: research

Interleukin-18 plays a dispensable role in murine and likely also human bone marrow failure
Acquired aplastic anemia (AA) is a bone marrow (BM) failure syndrome characterized by peripheral blood (PB) pancytopenia and BM hypoplasia [1-2]. Success of immunosuppressive therapy (IST), among other clinical and laboratory clues, is compelling evidence of immune pathophysiology of AA [3]. In most cases, AA is an immune-mediated disorder with active destruction of hematopoietic cells by effector T lymphocytes. Increased production of interferon gamma (IFN- γ), tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-2 by patients’ T cells suggests important roles for a type 1 immune response in BM hema...
Source: Experimental Hematology - October 11, 2018 Category: Hematology Authors: Zhijie Wu, Valentina Giudice, Jichun Chen, Wanling Sun, Zenghua Lin, Keyvan Keyvanfar, Nidhi Talasani, Sachiko Kajigaya, Xingmin Feng, Neal S. Young Tags: Regular Article Source Type: research

Distinct Pathways Affected by Menin versus MLL1/MLL2 in MLL-rearranged Acute Myeloid Leukemia
Patients with chromosomal translocations involving the Mixed Lineage Leukemia 1 gene (MLL, MLL1, KMT2A) represent an exception to overall favorable outcomes for children with acute leukemia [1]. Menin, encoded by the Men1 gene, is a tumor suppressor in neuroendocrine tissues but is essential for MLL1 fusion oncoprotein (MLL-FP)-mediated leukemogenesis. MLL-FP binding to Menin bridges an interaction with Lens Epithelium-Derived Growth Factor (LEDGF), which in turn binds histone H3 dimethyl lysine 36 (H3K36me2) modified chromatin [2,3]. (Source: Experimental Hematology)
Source: Experimental Hematology - October 10, 2018 Category: Hematology Authors: Yufei Chen, Kenneth L. Jones, Konstantinos Anastassiadis, Andrea Kranz, A. Francis Stewart, Jolanta Grembecka, Matthew Meyerson, Patricia Ernst Source Type: research

TCF4 promotes erythroid development
Transcription factor 4 (TCF4, ITF2, E2-2), is a basic helix-loop-helix (bHLH) transcription factor that belongs to the family of E-box binding proteins. These proteins recognize CANNTG (Ephrussi-box) DNA sequences, present in a variety of tissue-specific enhancers and promoters. E-proteins are widely expressed and can form both homodimers with other E-proteins or heterodimers with tissue specific bHLH proteins. Dimerization of bHLH transcription factors results in the formation of a four helix bundle, which allows the DNA binding domains to associate with the E-box recognition site, to regulate transcription [1]. (Source: ...
Source: Experimental Hematology - October 10, 2018 Category: Hematology Authors: Florentien E.M. in 't Hout, Jolanda van Duren, Davide Monteferrario, Emma Brinkhuis, Niccolo Mariani, Theresia M. Westers, Dana Chitu, Gorica Nikoloski, Arjan A. van de Loosdrecht, Bert A. van der Reijden, Joop H. Jansen, Gerwin Huls Tags: Brief report Source Type: research

Aptamer-based proteomics of serum and plasma in acquired aplastic anemia
Acquired aplastic anemia (AA), a bone marrow (BM) failure syndrome characterized by pancytopenia and BM hypocellularity, is caused by hematopoietic stem and progenitor cells (HSPCs) destruction by immune cells [1]. BM transplantation remains the first therapeutic choice for young patients with a matched sibling donor. Immunosuppressive therapies (IST), with or without the thrombopoietin (TPO) receptor agonist eltrombopag (EPAG), are considered the standard of care in older patients, and therapeutic option for younger patients without a matched sibling donor [1-2]. (Source: Experimental Hematology)
Source: Experimental Hematology - October 9, 2018 Category: Hematology Authors: Valentina Giudice, Ang élique Biancotto, Zhijie Wu, Foo Cheung, Julián Candia, Giovanna Fantoni, Sachiko Kajigaya, Olga Rios, Danielle Townsley, Xingmin Feng, Neal S. Young Tags: Regular Article Source Type: research

Skewed ratio between type 1 and type 2 calreticulin mutations in essential thrombocytosis patients with concomitant Janus kinase 2 V617F mutation
The classical Philadelphia-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), are a group of clonal hematopoietic stem cell disorders characterized by the overproduction of terminally differentiated and fully functional hematopoietic cells. Major molecular diagnostic criteria for the MPNs include the presence of somatic mutations in cardinal driver genes: Janus kinase 2 (JAK2) V617F or JAK2 exon 12 in PV and JAK2 V617F, calreticulin (CALR) exon 9, or XXXX (MPL) exon 10 in ET and PMF [1]. (Source: Experimental Hematology)
Source: Experimental Hematology - October 4, 2018 Category: Hematology Authors: Laura M. Haunstrup, Lene H. Ebbesen, Maria Hansen, Marianne T. Severinsen, Anni Aggerholm Tags: BRIEF COMMUNICATION Source Type: research

Skewed ratio between type 1 and type 2 CALR mutations in Essential Thrombocytosis patients with concomitant JAK2 V617F mutation
The classical Philadelphia-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF), are a group of clonal hematopoietic stem cell disorders characterized by the overproduction of terminally differentiated and fully functional hematopoietic cells. Major molecular diagnostic criteria for the MPNs, include presence of somatic mutations in cardinal driver genes; JAK2 V617F or JAK2 exon 12 in PV and JAK2 V617F, CALR exon 9 or MPL exon 10 in ET and PMF [1]. (Source: Experimental Hematology)
Source: Experimental Hematology - October 4, 2018 Category: Hematology Authors: Laura M. Haunstrup, Lene H. Ebbesen, Maria Hansen, Marianne T. Severinsen, Anni Aggerholm Source Type: research

Cover 2: Editorial Board
(Source: Experimental Hematology)
Source: Experimental Hematology - October 1, 2018 Category: Hematology Source Type: research

A rare subgroup of leukemia stem cells harbors relapse-inducing potential in acute lymphoblastic leukemia
After initially successful chemotherapy, relapse frequently jeopardizes the outcome of patients with acute leukemia. Because of their adverse characteristics of self-renewal and dormancy, leukemia stem cells have been hypothesized to play a critical role in resistance to antiproliferative chemotherapy and the development of relapse. The high abundance of stem-like cells in acute lymphoblastic leukemia (ALL), however, suggests that not all leukemia-initiating cells carry these adverse characteristics, complicating the biological characterization of relapse-inducing cells in this malignancy. (Source: Experimental Hematology)
Source: Experimental Hematology - September 24, 2018 Category: Hematology Authors: Daniela Senft, Irmela Jeremias Tags: REVIEW Source Type: research

The Human Cell Atlas Bone Marrow Single-Cell Interactive Web Portal
The advent of new innovative technologies for single-cell genomics provides nearly limitless opportunities for exploring tissue cellular variation at single-molecule resolution. Single-cell RNA profiling has already revealed hidden heterogeneity within presumed homogenous populations, novel intermediates and developmental trajectories [1-5]. Although thousands of cells can be readily captured and profiled with these technologies, the cellular composition of in vivo cellular niches are complex, currently requiring selective strategies for isolation, such as flow cytometry sorting and a priori defined surface markers to capt...
Source: Experimental Hematology - September 20, 2018 Category: Hematology Authors: Stuart Hay, Kyle Ferchen, Kashish Chetal, H. Leighton Grimes, Nathan Salomonis Source Type: research

A Fond Salute to George Stamatoyannopoulos – Scholar Leader Mentor Colleague Friend
George Stam, as the world came to know him, slipped away from us on June 16 of this year. This marked over half a century of major achievements that revolutionized our understanding of the science of genetics and hematology. His unique and persistent, typically impatient, approach to make progress was surpassed by none. He will also be remembered for his lifelong leadership and commitment to the pursuit of truth, to the creation of a deeper understanding of how blood cells are normally generated, and the development of better treatments for diseases that arise when this process goes awry. (Source: Experimental Hematology)
Source: Experimental Hematology - September 12, 2018 Category: Hematology Authors: Connie J. Eaves Source Type: research

Upregulated microRNA-146a expression induced by granulocyte colony-stimulating factor enhanced low-dosage chemotherapy response in aged acute myeloid leukemia patients
Acute myeloid leukemia (AML) is a heterogeneous group of aggressive malignancies characterized by the uncontrolled proliferation of leukemia cells. Among patients with AML younger than 60 years, the complete remission (CR) rate is approximately 60% and the 5-year overall survival (OS) is approximately 40% after intensive chemotherapy and progressive, supportive treatment [1]. Unfortunately, the median age of patients with AML is approximately 65 years [2] and the CR and long-term disease-free survival rates remain low in this population. (Source: Experimental Hematology)
Source: Experimental Hematology - September 9, 2018 Category: Hematology Authors: Xin Li, Lan Xu, Xianfu Sheng, Jiayi Cai, Jia Liu, Tingyu Yin, Fei Xiao, Fangyuan Chen, Hua Zhong Source Type: research

Upregulated microRNA-146a expression induced by granulocyte colony-stimulating factor-enhanced low-dosage chemotherapy response in aged acute myeloid leukemia patients
Acute myeloid leukemia (AML) is a heterogeneous group of aggressive malignancies characterized by the uncontrolled proliferation of leukemia cells. Among patients with AML younger than 60 years, the complete remission (CR) rate is approximately 60% and the 5-year overall survival (OS) is approximately 40% after intensive chemotherapy and progressive, supportive treatment [1]. Unfortunately, the median age of patients with AML is approximately 65 years [2] and the CR and long-term disease-free survival rates remain low in this population. (Source: Experimental Hematology)
Source: Experimental Hematology - September 9, 2018 Category: Hematology Authors: Xin Li, Lan Xu, Xianfu Shen, Jiayi Cai, Jia Liu, Tingyu Yin, Fei Xiao, Fangyuan Chen, Hua Zhong Source Type: research

Up-regulated miR-146a expression induced by G-CSF enhanced low dosage chemotherapy response in aged acute myeloid leukemia patients
Acute myeloid leukemia (AML) is a heterogeneous group of aggressive malignancies characterized by the uncontrolled proliferation of leukemia cells. Among patients with AML younger than 60 years, the complete remission rate is approximately 60% and the 5-year overall survival is approximately 40% after intensive chemotherapy and progressive, supportive treatment [1]. Unfortunately, the median age of patients with AML is approximately 65 years [2], and the complete remission and long-term disease-free survival rates remain low in this population. (Source: Experimental Hematology)
Source: Experimental Hematology - September 9, 2018 Category: Hematology Authors: Xin Li, Lan Xu, Xianfu Shen, Jiayi Cai, Jia Liu, Tingyu Yin, Fei Xiao, Fangyuan Chen, Hua Zhong Source Type: research

Platelet engraftment after allogenic stem cell transplantation is monitoredby digital polymerase chain reaction without interferencebyplatelet support
Leukocyte and platelet counts after transplantation with hematopoietic stem cells (HSCs) serve as an early and relevant sign for the success of transplantation. The time to leukocyte and platelet engraftment appears to be a valid predictor of the probability of complications in transplanted patients, especially for those receiving allogeneic HSC transplantation [1]. The Center for International Blood& Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation (EBMT) agree in the definition of leukocyte engraftment as the third day of 3 consecutive days with absolute neutrophil cou...
Source: Experimental Hematology - September 6, 2018 Category: Hematology Authors: Andrea Doescher, Jochen Casper, Doris Kraemer, Hans-Hermann Kapels, Eduard K. Petershofen, Thomas H. M üller Source Type: research

Platelet engraftment after allogenic stem cell transplantation is monitored by digital PCR without interference by platelet support
Leucocyte and platelet counts after transplantation with hematopoietic stem cells (HSC) serve as an early and relevant sign for the success of transplantation. The time to leucocyte and platelet engraftment appears to be a valid predictor of the probability of complications in transplanted patients and especially for allogeneic HSC transplantation.1 EBMT and CIBMTR agree in the definition of leucocyte engraftment as the third day of three consecutive days with absolute neutrophil counts (ANC)> 500/mm3. (Source: Experimental Hematology)
Source: Experimental Hematology - September 6, 2018 Category: Hematology Authors: Andrea Doescher, Jochen Casper, Doris Kraemer, Hans-Hermann Kapels, Eduard K Petershofen, Thomas H. M üller Source Type: research

Ponatinib evaluation and safety in real-life chronic myelogenous leukemia patients failing more than two tyrosine kinase inhibitors: The PEARL observational study
Chronic myelogenous leukemia (CML) is induced by the onset of a unique molecular hit, the BCR-ABL oncogene, in a discrete population of hematopoietic stem cells and results in a considerable expansion of the myeloid compartment, compromised apoptotic process, recirculation of progenitors, and genetic instability [1]. This chimeric oncogene is the consequence of a reciprocal translocation the t(9;22)(q34;q11), the Philadelphia (Ph) chromosome [1]. The first tyrosine kinase inhibitor (TKI), imatinib mesylate, was introduced in 1998 and reversed the poor prognosis of this disease, particularly in chronic phase (CP) [2]. (Sour...
Source: Experimental Hematology - September 5, 2018 Category: Hematology Authors: Ma ël Heiblig, Delphine Rea, Marie-Lorraine Chrétien, Aude Charbonnier, Philippe Rousselot, Valérie Coiteux, Martine Escoffre-Barbe, Viviane Dubruille, Françoise Huguet, Emilie Cayssials, Eric Hermet, Agnès Guerci-Bresler, Shanti Amé, Lucila Sackman Source Type: research

Ponatinib Evaluation And safety in Real Life CML patients failing ≥2 tyrosine kinase inhibitors: The PEARL observational study
Chronic myelogenous leukemia (CML) is induced by the onset of a unique molecular hit, the BCR-ABL oncogene, in a discrete population of hematopoietic stem cells and results in a considerable expansion of the myeloid compartment, compromised apoptotic process, recirculation of progenitors and genetic instability [1]. This chimeric oncogene is the consequence of a reciprocal translocation the t(9;22) (q34;q11), the Philadelphia chromosome [1]. The first tyrosine kinase inhibitor (TKI) imatinib mesylate, was introduced in 1998 and reversed the poor prognosis of this disease, particularly in chronic phase (CP) [2]. (Source: Ex...
Source: Experimental Hematology - September 5, 2018 Category: Hematology Authors: Ma ël Heiblig, Delphine Rea, Marie-Lorraine Chrétien, Aude Charbonnier, Philippe Rousselot, Valérie Coiteux, Martine Escoffre-Barbe, Viviane Dubruille, Françoise Huguet, Emilie Cayssials, Eric Hermet, Agnès Guerci-Bresler, Shanti Amé, Lucila Sackman Source Type: research

miR-217 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitors by targeting pro-oncogenic anterior gradient 2
Chronic myelogenous leukemia (CML), characterized by the presence of Philadelphia (Ph+) chromosome is a haematopoietic stem cell malignancy. Translocation of chromosome 9 and chromosome 22 leads to formation of BCR-ABL1 fusion gene, whose gene product drives and maintains pathogenesis of CML [1,2]. Tyrosine kinase inhibitors (TKIs) treatment have improved outcome of CML patients dramatically since its first application more than a decade ago [3]. Although receiving more potent second generation TKIs, such as dasatinib and nilotinib, some patients still experienced resistance and relapse [4,5]. (Source: Experimental Hematology)
Source: Experimental Hematology - September 5, 2018 Category: Hematology Authors: Bin Pan, Jing Yang, Xiangmin Wang, Kailin Xu, Takayuki Ikezoe Source Type: research

Long noncoding RNA HOTAIR promotes the self-renewal of leukemia stem cells through epigenetic silencing of p15
Acute myeloid leukemia (AML) is characterized by the blockage of differentiation and uncontrolled proliferation. Although conventional chemotherapy and stem cell transplantation markedly improve the overall survival (OS) in AML patients, half of adult patients and more than 80% of older patients (>60 years) die as a result of primary refractoriness, relapse, or treatment-related mortality [1]. Various genetic mutations, such as c-Kit, FLT3, and WT1, lead to the initiation and development of AML [2]. (Source: Experimental Hematology)
Source: Experimental Hematology - August 30, 2018 Category: Hematology Authors: Shenmeng Gao, Bin Zhou, Haiying Li, Xingzhou Huang, Yanfei Wu, Chongyun Xing, Xiaozhuo Yu, Yanhong Ji Source Type: research

Long non-coding RNA HOTAIR promotes the self-renewal of leukemia stem cell through epigenetic silencing of p15
Acute myeloid leukemia (AML) is characterized by the blockage of differentiation and uncontrolled proliferation. Although conventional chemotherapy and stem cell transplantation markedly improve the overall survival in AML patients, half adult patients and above 80% older patients (>60 years) are fatal due to primary refractoriness, relapse, or treatment-related mortality [1]. Various genetic mutations, such as c-Kit, FLT3, and WT1, lead to the initiation and development of AML [2]. However, increasing studies have demonstrated that epigenetic modulations, such as non-coding RNAs including microRNAs and long non-coding ...
Source: Experimental Hematology - August 30, 2018 Category: Hematology Authors: Shenmeng Gao, Bin Zhou, Haiying Li, Xingzhou Huang, Yanfei Wu, Chongyun Xing, Xiaozhuo Yu, Yanhong Ji Source Type: research

Comparative utility of NRG and NRGS mice for the study of normal hematopoiesis, leukemogenesis, and therapeutic response
Immune-deficient mice have revolutionized biomedical research, including the study of both normal human hematopoiesis and leukemogenesis [1 –3]. Capable of harboring both normal and malignant human xenografts without rejection, highly immune-deficient mice are indispensable in hematological research, allowing differentiation and proliferation of these cells in vivo [4]. Xenograft mouse models consistently better predict the success of experimental chemotherapeutics in clinical trials [5], likely because of the complex and dynamic interaction between the bone marrow (BM) microenvironment and heterogeneous populations ...
Source: Experimental Hematology - August 17, 2018 Category: Hematology Authors: Aditya Barve, Lavona Casson, Maxwell Krem, Mark Wunderlich, James C. Mulloy, Levi J. Beverly Source Type: research

Oral Administration of the LSD1 Inhibitor ORY-3001 Increases Fetal Hemoglobin in Sickle Cell Mice and Baboons
The β-hemoglobinopathies, consisting of sickle cell disease (SCD) and the β-thalassemias, are the most common genetic diseases worldwide. These syndromes cause widespread suffering and significant reduction in lifespan in patients. The β-thalassemia syndromes comprise a spectrum of disorders characte rized by deficiencies in the production of the adult β-globin chain [1]. Increased expression of the fetal γ-globin chains and Fetal Hemoglobin [(HbF(α2γ2)] can augment reduced β-globin chain deficiencies and is therefore considered a desirable therapeutic target that can ameliorate t...
Source: Experimental Hematology - August 17, 2018 Category: Hematology Authors: Angela Rivers, Kestis Vaitkus, Ramasamy Jagadeeswaran, Maria Armila Ruiz, Vinzon Ibanez, Filippo Ciceri, Fernando Cavalcanti, Robert E. Molokie, Yogen Saunthararajah Y, James Douglas Engel, Joseph DeSimone J, Donald Lavelle Tags: Brief Communication Source Type: research

Comparative utility of NRG and NRGS mice for the study of normal hematopoiesis, leukemogenesis and therapeutic response
Immune deficient mice have revolutionized biomedical research, including the study of both normal human hematopoiesis and leukemogenesis.[1-3] Capable of harboring both normal and malignant human xenografts without rejection, highly immune deficient mice are indispensable in hematological research allowing differentiation and proliferation of these cells in vivo.[4] Xenograft mouse models consistently better predict the success of experimental chemotherapeutics in clinical trials [5], likely due to the complex and dynamic interaction between the bone marrow (BM) microenvironment and heterogeneous populations of leukemic ce...
Source: Experimental Hematology - August 17, 2018 Category: Hematology Authors: Aditya Barve, Lavona Casson, Maxwell Krem, Mark Wunderlich, James C. Mulloy, Levi J. Beverly Source Type: research

Epigenetic modification enhances the cytotoxicity of busulfan and4-hydroperoxycyclophosphamide in AML cells
Busulfan (Bu) is a bifunctional DNA-alkylating agent commonly used in combination with other agents for high-dose pretransplantation conditioning therapy for hematopoietic stem cell transplantation (HSCT) [1]. Its combination with cyclophosphamide (Cy) has been used as an alternative to a Cy plus total body irradiation (Cy+TBI)-containing myeloablative regimen and found to be effective for acute leukemias [2 –7]. The “BuCy2” preparative regimen is more effective than Cy+TBI in patients ≤40 years old [6,8]. (Source: Experimental Hematology)
Source: Experimental Hematology - August 10, 2018 Category: Hematology Authors: Benigno C. Valdez, Xiaowen Tang, Yang Li, David Murray, Yan Liu, Uday Popat, Richard E. Champlin, Borje S. Andersson Source Type: research

Epigenetic modification enhances the cytotoxicity of busulfan and 4-hydroperoxycyclophosphamide in AML cells
Busulfan (Bu) is a bifunctional DNA alkylating agent commonly used in combination with other agents for high-dose pre-transplant conditioning therapy for hematopoietic stem cell transplantation (HSCT) [1]. Its combination with cyclophosphamide (Cy) has been used as an alternative to a Cy-total body irradiation (TBI)-containing myeloablative regimen and found to be effective for acute leukemias [2-7]. The “BuCy2” preparative regimen is more effective than Cy+TBI in patients ≤ 40 years old [6,8]. However, the “BuCy2” regimen is commonly associated with high non-relapse mortality [9]. (Source: ...
Source: Experimental Hematology - August 10, 2018 Category: Hematology Authors: Benigno C. Valdez, Xiaowen Tang, Yang Li, David Murray, Yan Liu, Uday Popat, Richard E. Champlin, Borje S. Andersson Source Type: research

Fluorescent genetic barcoding for cellular multiplex analyses
Hematopoiesis depends on the hierarchical production of mature cells from a pool of self-renewing hematopoietic stem cells (HSC). Due to their high regenerative capacity, great interest focuses on the understanding of HSC biology, which can be best assessed in functional transplantation assays that allow for the read-out of HSC numbers and their potential to produce cells of disparate lineages. To track individual HSC fate decisions, initial transplantation studies employed retroviral gene marking of bulk cells and subsequent Southern Blot analyses to assess clonal hematopoietic contributions [1-3]. (Source: Experimental Hematology)
Source: Experimental Hematology - August 8, 2018 Category: Hematology Authors: Tobias Maetzig, Michael Morgan, Axel Schambach Tags: Review Source Type: research