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Forever young: 44 years old and still going strong
Experimental Hematology 2016;44:641–643
Forever young: 44 years old and still going strong In the fifties, driven by the need to understand the biologic consequences of atomic energy and how to exploit this knowledge for clinical purposes, hematologists were at the forefront of revolutionary research that transformed a descriptive discipline based on morphological observations to the exciting discipline of experimental hematology that we know today. The promise of this early work gave birth to the journal of Experimental Hematology. As illustrated by the brief biosketch of Dr. van Bekkum, one of the founding fathers of the International Society of Experimental Hematology (ISEH), included in the review by Vriesendorp and Heidt [1], hematologists trained during World War II were all marked by hardship and psychological traumas that committed them to an openminded, multi-ethnical, and civil-rights–oriented attitude. This attitude inspired them to create a journal that would not only be scientifically sound, but would also provide a ‘‘hub’’ for innovative concepts that might be considered ‘‘heretical’’ and rejected by mainstream journals. The first issue of Experimental Hematology was published 44 years ago, in 1972, with the mission to divulge, in an international arena, cutting-edge research in the emerging field of experimental hematology. The scientific themes covered in the early days are still covered today: experimental stem cell transplantation, normal and malignant hematopoiesis, stem cells and their microenvironment, and immunology and immunotherapy. Under the leadership of a series of illustrious editors [Lyle R. Heim (1973–1983), Dane R. Boggs (1984), Michael P. McGarry (1984–1985), Eugene P. Cronkite (1985–1989), Peter J. Quesenberry (1990–1998), Ronald Hoffman (1999–2003), Esmail D. Zanjani (2004–2010), and now Keith Humphries (2011– present)], the journal has remained true to its original mission and, over the years, has published numerous high-quality, out-of-the-box papers, some which unfortunately are not presently available online. These articles set the stage for scientific questions that are still actively pursued and sparked the development of innovative diagnostic and therapeutic tools. For their significance and impact, these articles deserve to be called ‘‘citation classics.’’ This issue of Experimental Hematology honors eight such articles published by the journal that meet this Offprint requests to: Anna Rita Migliaccio, PhD, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1079, New York, NY 10029; E-mail: annarita.migliaccio@ mssm.edu
definition. Six additional original research reports, three submitted under the new fast-track option, appear in this same issue and further highlight the important continuing contributions in areas that can be traced back to these citation classics. My own review [2] honors an article published in 1975 by Dr. Cronkite, a founding father of ISEH and past editor of the journal, in the area of experimental stem cell transplantation. The article by Dr. Cronkite provided proof-ofprinciple that donor hematopoietic stem cells may engraft nonablated recipients provided that they have an advantage over the host stem cells [3]. Further studies from investigators at the Quesenberry laboratory and my own defined the nature of the stem cell advantage that allows engraftment in transfused recipients and mechanisms that specifically deplete their lymphocytes, preventing graft-versus-host disease. These concepts have advanced the field by allowing for the development of xenograft models with which to study human hematopoiesis in nonstressed recipients and procedures to transfuse healthy stem cells in patients carrying inherited genetic disorders with limited toxicity (and that are affordable in third-world countries). Two reviews [4,5] are prompted by citation classics articles published in the area of normal hematopoiesis. The review by Koury [4] honors Dr. Makio Ogawa for an article published in 1977 by Hara and Ogawa that for the first time described the effects of erythropoietic stimulation and suppression on the frequency, cell-cycle state, and location of erythroid progenitors defined on the basis of colonyforming assays in mice [6]. The paper by Papayannopoulou and Kaushansky [5] describes important scientific developments stemming from their article published in 1996 that demonstrated for the first time the existence of human progenitor cells giving rise to colonies containing both erythroid and megakaryocytic cells and how the fate of these cells is affected by the synergistic action of erythropoietin and thrombopoietin [7]. The article by Hara and Ogawa [6] drove the discovery of erythroid-stimulating agents for the treatment of anemia and the article by Papayannopoulou et al. [7] led to experiments that clarified the driver role exerted by mutations in the signaling pathway of erythropoietin and the thrombopoietin receptor for the pathogenesis of congenic and acquired erythrocytosis. Concepts from these two citation classics continue to guide the discovery of novel erythropoiesis stimulating agents (ESAs). This is illustrated by new findings from the Wojchowski laboratory [8] on novel EPO receptor interactions with a prototypic synthetic dimeric ESA. As discussed in the reviews by Wang et al. [9] and Shimizu and Yamamoto [10], Experimental Hematology
0301-472X/$ - see front matter. Copyright Ó 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.exphem.2016.06.004
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Editorial/ Experimental Hematology 2016;44:641–643
has published several citation classics articles in the field of malignant hematopoiesis. The review by Wang et al. [9] discusses research stemming from an article published in the journal by Kralovics et al. [11] in 2002, which described the important pathological consequences of what was considered a hypothetical event for the duplication of somatic cells: chromosome crossing over. In their article, Kralovics et al. [11] showed that crossing over may also occur in somatic cells, leading them to acquire uniparental disomy; that is, to lose heterozygosity and to become disomic for one of the two alleles. They found that, in polycythemia vera, stem cells frequently acquire uniparental disomy at regions of chromosome 9p that include JAK2. More recent studies driven by this observation showed that gain-offunction mutations in JAK2 are drivers for the development of myeloproliferative neoplasms, including polycythemia vera. Moreover, the acquired parental disomy discovered by Kralovics et al. [11] favors accumulation over time of stem cells homozygous for these mutations, contributing to disease progression. The fact that acquired uniparental disomy is not detectable by comparative genome hybridization led to the development and systematic application of genome-wide single-nucleotide polymorphism arrays. This technique is revolutionizing the diagnosis, not only of myeloproliferative neoplasms, but also of other cancers. The use of this exciting new technology is an active area of research because it offers the promise of personalized drug targeting and thus may improve therapy of these diseases. This technique is also increasing the power to detect novel mutations in cancer. The original research article published in this issue by Eckstein et al. [12] from the laboratory of Dr. Margaret A. Goodell, a former president of the society, has applied the technology to discover novel mutations in a rare leukemia: mixed-phenotype acute leukemia. Another innovative concept that stemmed from a citation classics article published in the malignant hematopoiesis section of the journal is that driver mutations may lead to leukemia by activating a mechanism that alters, either at the transcriptional or translational level, the expression of transcription factors. As nicely reviewed by Shimizu and Yamamoto [10], a citation classics article published by them in Experimental Hematology showed for the first time that a hypomorphic mutation in the gene encoding the transcription factor GATA1 induces a fatal, transplantable erythroleukemia under stress conditions in mice [13]. Although mutations in the regulatory regions of GATA1 have not yet been identified in human leukemias, increasing evidence implicates the hypomorphic functions of GATA1, induced either by mutations in genes that exert an epigenomic control of its transcription or in genes that impair the translation of its mRNA by the ribosome machinery, in malignant and nonmalignant disorders of erythropoiesis. In addition to GATA1, this mechanism may induce leukemia by altering the expression of additional genes, as nicely
demonstrated by the article from Kadono et al. [14], reporting ribosomopathy as a driver force in acute myeloid leukemia associated with the DDX41 p.R525H mutation. Experimental Hematology has hosted numerous articles in the area of stem cells dedicated to the identification and characterization of these cells in numerous organisms. The review by Jung et al. [15] stems from a citation classics article that showed for the first time that the numbers and functions of hematopoietic stem cells change with age in a fashion dependent on the genetic background of the host [16]. This observation led to the identification of the polycomb family of genes. These genes encode proteins that mediate the epigenetic changes occurring in the hematopoietic stem cell compartment with age. These changes may reduce the numbers of hematopoietic stem cell clones active in an organism with age, explaining the old observation that women lose G6PD heterozygosity as they age. These changes may lead to the selection of stem cell clones that are more susceptible to transformation events and that, once transformed, may accumulate additional mutations that lead to disease progression and acquisition of resistance to cytotoxic therapies. This knowledge has inspired the development of epigenetic therapies to treat leukemia. An example of such therapies, originally defined by Paul Marks as ‘‘differentiation therapies,’’ is nicely discussed in the article by Botezatu et al. [17] in this issue. The review by Alexander [18] honors an article by Donald Metcalf, another founding father of ISEH, which was published in 1987 in the field of microenvironment and the niche [19]. As well illustrated by the numerous obituaries published in his honor the year after his death, Dr. Metcalf discovered several of the growth factors produced by the microenvironment to control the fate of the hematopoietic stem cells, but GM-CSF (also known as CSF3) was the one he was particularly fond of. This article by Metcalf et al. [19] reported for the first time the effects exerted by recombinant GM-CSF when injected in mice. It is particularly timely to honor this work given the fact that GM-CSF has been finally approved for clinical use in humans. The original research article by Chretien et al. [20] in this issue, however, highlights how much we still do not know about the control of the late stages of granulomonocytopoiesis and how much work must still be done to complete Dr. Metcalf’s mission in this field. Last but not least, the review by Vriesendorp and Heidt [1] honors a citation classics article that may be considered the starting point of the application of immunology and immunotherapy to cell therapy. This article detailed for the first time procedures to reduce the consequences of graft-versus-host disease in dogs [21]. The review describes how graft-versus-host disease was discovered and how this discovery favored the development of more effective bone marrow transplantation and blood transfusion procedures. Vriesendorp and Heidt also honor another citation classics article published in the journal in 1973 by Dicke et al. [22]
Editorial/ Experimental Hematology 2016;44:641–643
from the van Bekkum laboratory. This article was the first to describe the physical isolation and morphologic characterization of hematopoietic stem cells from rodents and primates. The prospective isolation and characterization of hematopoietic stem cells is still an area of active investigation that requires the development of novel, more specific tracking models. This is demonstrated by the original research reported by Perez-Cunningham et al. [23] in this issue, which describes a novel mouse model in which a fluorescent marker may label either different hematopoietic stem cell subsets or the hematopoietic stem cells, depending on the driver (either VAV or FLT2) that sustains its expression. I would like to end this introduction with a comment made by the current editor-in-chief of Experimental Hematology, Dr. Keith Humphries: ‘‘It is all about the concepts and advances that continue to this day. The field remains vibrant and the journal remains vital to spreading the story.’’ Anna Rita Migliaccio Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY References 1. Vriesendorp HM, Heidt PJ. History of graft-versus-host disease. Exp Hematol. 2016;44:674–688. 2. Migliaccio AR. To condition or not to conditiondThat is the question: The evolution of nonmyeloablative conditions for transplantation. Exp Hematol. 2016;44:706–712. 3. Cronkite EP, Bullis JE, Brecher G. Marrow transfusions increase pluripotent stem cells in normal hosts. Exp Hematol. 1985;13:802–805. 4. Koury MJ. Tracking erythroid progenitor cells in times of need and times of plenty. Exp Hematol. 2016;44:653–663. 5. Papayannopoulou T, Kaushansky K. Evolving insights into the synergy between erythropoietin and thrombopoietin and the bipotent erythroid/megakaryocytic progenitor cell. Exp Hematol. 2016;44: 664–668. 6. Hara H, Ogawa M. Erythropoietic precursors in mice under erythropoietic stimulation and suppression. Exp Hematol. 1977;5:141–148. 7. Papayannopoulou T, Brice M, Farrer D, Kaushansky K. Insights into the cellular mechanisms of erythropoietin-thrombopoietin synergy. Exp Hematol. 1996;24:660–669.
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8. Verma R, Green JM, Schatz PJ, Wojchowski DM. A dimeric peptide with erythropoiesis-stimulating activity uniquely affects erythropoietin receptor ligation and cell surface expression. Exp Hematol. 2016;44:765–769. 9. Wang L, Wheeler DA, Prchal JT. Acquired uniparental disomy of chromosome 9p in hematologic malignancies. Exp Hematol. 2016; 44:644–652. 10. Shimizu R, Yamamoto M. GATA-related hematologic disorders. Exp Hematol. 2016;44:696–705. 11. Kralovics R, Guan Y, Prchal JT. Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp Hematol. 2002;30:229–236. 12. Eckstein OS, Wang L, Punia JN, et al. Mixed-phenotype acute leukemia (MPAL) exhibits frequent mutations in DNMT3A and activated signaling genes. Exp Hematol. 2016;44:740–744. 13. Abe K, Shimizu R, Pan X, Hamada H, Yoshikawa H, Yamamoto M. Stem cells of GATA1-related leukemia undergo pernicious changes after 5-fluorouracil treatment. Exp Hematol. 2009;37:435–445. 14. Kadono M, Kanai A, Nagamachi A, et al. Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia. Exp Hematol. 2016;44:745–754. 15. Jung J, Buisman S, de Haan G. Hematopoiesis during development, aging, and disease. Exp Hematol. 2016;44:689–695. 16. Van Zant G, de Haan G, Rich IN. Alternatives to stem cell renewal from a developmental viewpoint. Exp Hematol. 1997;25:187–192. 17. Botezatu L, Michel LC, Helness A, et al. Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML. Exp Hematol. 2016;44:713–726. 18. Alexander WS. In vivo at last: Demonstrating the biological credentials and clinical potential of GM-CSF. Exp Hematol. 2016;44: 669–673. 19. Metcalf D, Begley CG, Williamson DJ, et al. Hemopoietic responses in mice injected with purified recombinant murine GM-CSF. Exp Hematol. 1987;15:1–9. 20. Chretien ML, Legouge C, Martin RZ, et al. Trim33/Tif1g is involved in late stages of granulomonopoiesis in mice. Exp Hematol. 2016;44: 727–739. 21. Vriesendorp H, Heidt PJ, Zurcher C. Gastrointestinal decontamination of dogs treated with total body irradiation and bone marrow transplantation. Exp Hematol. 1981;9:904–916. 22. Dicke KA, van Noord MJ, van Bekkum DW. Attempts at morphological identification of the hemopoietic stem cell in rodents and primates. Exp Hematol. 1973;1:36–45. 23. Perez-Cunningham J, Boyer SW, Landon M, Forsberg EC. Hematopoietic stem cell-specific GFP-expressing transgenic mice generated by genetic excision of a pan-hematopoietic reporter gene. Exp Hematol. 2016;44:755–764.
Forever young: 44 years old and still going strong In the fifties, driven by the need to understand the biologic consequences of atomic energy and how to exploit this knowledge for clinical purposes, hematologists were at the forefront of revolutionary research that transformed a descriptive discipline based on morphological observations to the exciting discipline of experimental hematology that we know today. The promise of this early work gave birth to the journal of Experimental Hematology. As illustrated by the brief biosketch of Dr. van Bekkum, one of the founding fathers of the International Society of Experimental Hematology (ISEH), included in the review by Vriesendorp and Heidt [1], hematologists trained during World War II were all marked by hardship and psychological traumas that committed them to an openminded, multi-ethnical, and civil-rights–oriented attitude. This attitude inspired them to create a journal that would not only be scientifically sound, but would also provide a ‘‘hub’’ for innovative concepts that might be considered ‘‘heretical’’ and rejected by mainstream journals. The first issue of Experimental Hematology was published 44 years ago, in 1972, with the mission to divulge, in an international arena, cutting-edge research in the emerging field of experimental hematology. The scientific themes covered in the early days are still covered today: experimental stem cell transplantation, normal and malignant hematopoiesis, stem cells and their microenvironment, and immunology and immunotherapy. Under the leadership of a series of illustrious editors [Lyle R. Heim (1973–1983), Dane R. Boggs (1984), Michael P. McGarry (1984–1985), Eugene P. Cronkite (1985–1989), Peter J. Quesenberry (1990–1998), Ronald Hoffman (1999–2003), Esmail D. Zanjani (2004–2010), and now Keith Humphries (2011– present)], the journal has remained true to its original mission and, over the years, has published numerous high-quality, out-of-the-box papers, some which unfortunately are not presently available online. These articles set the stage for scientific questions that are still actively pursued and sparked the development of innovative diagnostic and therapeutic tools. For their significance and impact, these articles deserve to be called ‘‘citation classics.’’ This issue of Experimental Hematology honors eight such articles published by the journal that meet this Offprint requests to: Anna Rita Migliaccio, PhD, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1079, New York, NY 10029; E-mail: annarita.migliaccio@ mssm.edu
definition. Six additional original research reports, three submitted under the new fast-track option, appear in this same issue and further highlight the important continuing contributions in areas that can be traced back to these citation classics. My own review [2] honors an article published in 1975 by Dr. Cronkite, a founding father of ISEH and past editor of the journal, in the area of experimental stem cell transplantation. The article by Dr. Cronkite provided proof-ofprinciple that donor hematopoietic stem cells may engraft nonablated recipients provided that they have an advantage over the host stem cells [3]. Further studies from investigators at the Quesenberry laboratory and my own defined the nature of the stem cell advantage that allows engraftment in transfused recipients and mechanisms that specifically deplete their lymphocytes, preventing graft-versus-host disease. These concepts have advanced the field by allowing for the development of xenograft models with which to study human hematopoiesis in nonstressed recipients and procedures to transfuse healthy stem cells in patients carrying inherited genetic disorders with limited toxicity (and that are affordable in third-world countries). Two reviews [4,5] are prompted by citation classics articles published in the area of normal hematopoiesis. The review by Koury [4] honors Dr. Makio Ogawa for an article published in 1977 by Hara and Ogawa that for the first time described the effects of erythropoietic stimulation and suppression on the frequency, cell-cycle state, and location of erythroid progenitors defined on the basis of colonyforming assays in mice [6]. The paper by Papayannopoulou and Kaushansky [5] describes important scientific developments stemming from their article published in 1996 that demonstrated for the first time the existence of human progenitor cells giving rise to colonies containing both erythroid and megakaryocytic cells and how the fate of these cells is affected by the synergistic action of erythropoietin and thrombopoietin [7]. The article by Hara and Ogawa [6] drove the discovery of erythroid-stimulating agents for the treatment of anemia and the article by Papayannopoulou et al. [7] led to experiments that clarified the driver role exerted by mutations in the signaling pathway of erythropoietin and the thrombopoietin receptor for the pathogenesis of congenic and acquired erythrocytosis. Concepts from these two citation classics continue to guide the discovery of novel erythropoiesis stimulating agents (ESAs). This is illustrated by new findings from the Wojchowski laboratory [8] on novel EPO receptor interactions with a prototypic synthetic dimeric ESA. As discussed in the reviews by Wang et al. [9] and Shimizu and Yamamoto [10], Experimental Hematology
0301-472X/$ - see front matter. Copyright Ó 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.exphem.2016.06.004
642
Editorial/ Experimental Hematology 2016;44:641–643
has published several citation classics articles in the field of malignant hematopoiesis. The review by Wang et al. [9] discusses research stemming from an article published in the journal by Kralovics et al. [11] in 2002, which described the important pathological consequences of what was considered a hypothetical event for the duplication of somatic cells: chromosome crossing over. In their article, Kralovics et al. [11] showed that crossing over may also occur in somatic cells, leading them to acquire uniparental disomy; that is, to lose heterozygosity and to become disomic for one of the two alleles. They found that, in polycythemia vera, stem cells frequently acquire uniparental disomy at regions of chromosome 9p that include JAK2. More recent studies driven by this observation showed that gain-offunction mutations in JAK2 are drivers for the development of myeloproliferative neoplasms, including polycythemia vera. Moreover, the acquired parental disomy discovered by Kralovics et al. [11] favors accumulation over time of stem cells homozygous for these mutations, contributing to disease progression. The fact that acquired uniparental disomy is not detectable by comparative genome hybridization led to the development and systematic application of genome-wide single-nucleotide polymorphism arrays. This technique is revolutionizing the diagnosis, not only of myeloproliferative neoplasms, but also of other cancers. The use of this exciting new technology is an active area of research because it offers the promise of personalized drug targeting and thus may improve therapy of these diseases. This technique is also increasing the power to detect novel mutations in cancer. The original research article published in this issue by Eckstein et al. [12] from the laboratory of Dr. Margaret A. Goodell, a former president of the society, has applied the technology to discover novel mutations in a rare leukemia: mixed-phenotype acute leukemia. Another innovative concept that stemmed from a citation classics article published in the malignant hematopoiesis section of the journal is that driver mutations may lead to leukemia by activating a mechanism that alters, either at the transcriptional or translational level, the expression of transcription factors. As nicely reviewed by Shimizu and Yamamoto [10], a citation classics article published by them in Experimental Hematology showed for the first time that a hypomorphic mutation in the gene encoding the transcription factor GATA1 induces a fatal, transplantable erythroleukemia under stress conditions in mice [13]. Although mutations in the regulatory regions of GATA1 have not yet been identified in human leukemias, increasing evidence implicates the hypomorphic functions of GATA1, induced either by mutations in genes that exert an epigenomic control of its transcription or in genes that impair the translation of its mRNA by the ribosome machinery, in malignant and nonmalignant disorders of erythropoiesis. In addition to GATA1, this mechanism may induce leukemia by altering the expression of additional genes, as nicely
demonstrated by the article from Kadono et al. [14], reporting ribosomopathy as a driver force in acute myeloid leukemia associated with the DDX41 p.R525H mutation. Experimental Hematology has hosted numerous articles in the area of stem cells dedicated to the identification and characterization of these cells in numerous organisms. The review by Jung et al. [15] stems from a citation classics article that showed for the first time that the numbers and functions of hematopoietic stem cells change with age in a fashion dependent on the genetic background of the host [16]. This observation led to the identification of the polycomb family of genes. These genes encode proteins that mediate the epigenetic changes occurring in the hematopoietic stem cell compartment with age. These changes may reduce the numbers of hematopoietic stem cell clones active in an organism with age, explaining the old observation that women lose G6PD heterozygosity as they age. These changes may lead to the selection of stem cell clones that are more susceptible to transformation events and that, once transformed, may accumulate additional mutations that lead to disease progression and acquisition of resistance to cytotoxic therapies. This knowledge has inspired the development of epigenetic therapies to treat leukemia. An example of such therapies, originally defined by Paul Marks as ‘‘differentiation therapies,’’ is nicely discussed in the article by Botezatu et al. [17] in this issue. The review by Alexander [18] honors an article by Donald Metcalf, another founding father of ISEH, which was published in 1987 in the field of microenvironment and the niche [19]. As well illustrated by the numerous obituaries published in his honor the year after his death, Dr. Metcalf discovered several of the growth factors produced by the microenvironment to control the fate of the hematopoietic stem cells, but GM-CSF (also known as CSF3) was the one he was particularly fond of. This article by Metcalf et al. [19] reported for the first time the effects exerted by recombinant GM-CSF when injected in mice. It is particularly timely to honor this work given the fact that GM-CSF has been finally approved for clinical use in humans. The original research article by Chretien et al. [20] in this issue, however, highlights how much we still do not know about the control of the late stages of granulomonocytopoiesis and how much work must still be done to complete Dr. Metcalf’s mission in this field. Last but not least, the review by Vriesendorp and Heidt [1] honors a citation classics article that may be considered the starting point of the application of immunology and immunotherapy to cell therapy. This article detailed for the first time procedures to reduce the consequences of graft-versus-host disease in dogs [21]. The review describes how graft-versus-host disease was discovered and how this discovery favored the development of more effective bone marrow transplantation and blood transfusion procedures. Vriesendorp and Heidt also honor another citation classics article published in the journal in 1973 by Dicke et al. [22]
Editorial/ Experimental Hematology 2016;44:641–643
from the van Bekkum laboratory. This article was the first to describe the physical isolation and morphologic characterization of hematopoietic stem cells from rodents and primates. The prospective isolation and characterization of hematopoietic stem cells is still an area of active investigation that requires the development of novel, more specific tracking models. This is demonstrated by the original research reported by Perez-Cunningham et al. [23] in this issue, which describes a novel mouse model in which a fluorescent marker may label either different hematopoietic stem cell subsets or the hematopoietic stem cells, depending on the driver (either VAV or FLT2) that sustains its expression. I would like to end this introduction with a comment made by the current editor-in-chief of Experimental Hematology, Dr. Keith Humphries: ‘‘It is all about the concepts and advances that continue to this day. The field remains vibrant and the journal remains vital to spreading the story.’’ Anna Rita Migliaccio Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY References 1. Vriesendorp HM, Heidt PJ. History of graft-versus-host disease. Exp Hematol. 2016;44:674–688. 2. Migliaccio AR. To condition or not to conditiondThat is the question: The evolution of nonmyeloablative conditions for transplantation. Exp Hematol. 2016;44:706–712. 3. Cronkite EP, Bullis JE, Brecher G. Marrow transfusions increase pluripotent stem cells in normal hosts. Exp Hematol. 1985;13:802–805. 4. Koury MJ. Tracking erythroid progenitor cells in times of need and times of plenty. Exp Hematol. 2016;44:653–663. 5. Papayannopoulou T, Kaushansky K. Evolving insights into the synergy between erythropoietin and thrombopoietin and the bipotent erythroid/megakaryocytic progenitor cell. Exp Hematol. 2016;44: 664–668. 6. Hara H, Ogawa M. Erythropoietic precursors in mice under erythropoietic stimulation and suppression. Exp Hematol. 1977;5:141–148. 7. Papayannopoulou T, Brice M, Farrer D, Kaushansky K. Insights into the cellular mechanisms of erythropoietin-thrombopoietin synergy. Exp Hematol. 1996;24:660–669.
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8. Verma R, Green JM, Schatz PJ, Wojchowski DM. A dimeric peptide with erythropoiesis-stimulating activity uniquely affects erythropoietin receptor ligation and cell surface expression. Exp Hematol. 2016;44:765–769. 9. Wang L, Wheeler DA, Prchal JT. Acquired uniparental disomy of chromosome 9p in hematologic malignancies. Exp Hematol. 2016; 44:644–652. 10. Shimizu R, Yamamoto M. GATA-related hematologic disorders. Exp Hematol. 2016;44:696–705. 11. Kralovics R, Guan Y, Prchal JT. Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp Hematol. 2002;30:229–236. 12. Eckstein OS, Wang L, Punia JN, et al. Mixed-phenotype acute leukemia (MPAL) exhibits frequent mutations in DNMT3A and activated signaling genes. Exp Hematol. 2016;44:740–744. 13. Abe K, Shimizu R, Pan X, Hamada H, Yoshikawa H, Yamamoto M. Stem cells of GATA1-related leukemia undergo pernicious changes after 5-fluorouracil treatment. Exp Hematol. 2009;37:435–445. 14. Kadono M, Kanai A, Nagamachi A, et al. Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia. Exp Hematol. 2016;44:745–754. 15. Jung J, Buisman S, de Haan G. Hematopoiesis during development, aging, and disease. Exp Hematol. 2016;44:689–695. 16. Van Zant G, de Haan G, Rich IN. Alternatives to stem cell renewal from a developmental viewpoint. Exp Hematol. 1997;25:187–192. 17. Botezatu L, Michel LC, Helness A, et al. Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML. Exp Hematol. 2016;44:713–726. 18. Alexander WS. In vivo at last: Demonstrating the biological credentials and clinical potential of GM-CSF. Exp Hematol. 2016;44: 669–673. 19. Metcalf D, Begley CG, Williamson DJ, et al. Hemopoietic responses in mice injected with purified recombinant murine GM-CSF. Exp Hematol. 1987;15:1–9. 20. Chretien ML, Legouge C, Martin RZ, et al. Trim33/Tif1g is involved in late stages of granulomonopoiesis in mice. Exp Hematol. 2016;44: 727–739. 21. Vriesendorp H, Heidt PJ, Zurcher C. Gastrointestinal decontamination of dogs treated with total body irradiation and bone marrow transplantation. Exp Hematol. 1981;9:904–916. 22. Dicke KA, van Noord MJ, van Bekkum DW. Attempts at morphological identification of the hemopoietic stem cell in rodents and primates. Exp Hematol. 1973;1:36–45. 23. Perez-Cunningham J, Boyer SW, Landon M, Forsberg EC. Hematopoietic stem cell-specific GFP-expressing transgenic mice generated by genetic excision of a pan-hematopoietic reporter gene. Exp Hematol. 2016;44:755–764.