From www.bloodjournal.org by guest on September 11, 2016. For personal use only. 3674
BLOOD, 5 JUNE 2014 x VOLUME 123, NUMBER 23
CORRESPONDENCE
4. ENCODE Project Consortium. A user’s guide to the Encyclopedia of DNA Elements (ENCODE). PLoS Biol. 2011;9(4):e1001046. 5. Brune V, Tiacci E, Pfeil I, et al. Origin and pathogenesis of nodular lymphocytepredominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med. 2008;205(10):2251-2268. 6. Hall A, Karplus PA, Poole LB. Typical 2-Cys peroxiredoxins—structures, mechanisms and functions. FEBS J. 2009;276(9):2469-2477.
7. Giefing M, Winoto-Morbach S, Sosna J, et al. Hodgkin-Reed-Sternberg cells in classical Hodgkin lymphoma show alterations of genes encoding the NADPH oxidase complex and impaired reactive oxygen species synthesis capacity. PLoS ONE. 2013;8(12): e84928.
© 2014 by The American Society of Hematology
To the editor: Phenotypically aberrant clonal T cells in the lungs of patients with type II refractory celiac disease Type II refractory celiac disease (RCD II) is a rare condition characterized by a massive accumulation of intraepithelial lymphocytes with a natural killer/T phenotype and containing clonal T-cell rearrangements.1 Its severe prognosis is largely due to the development of an aggressive enteropathy-type–associated T-cell lymphoma (EATL). RCD II is a diffuse digestive but also extradigestive disease.2 Various pulmonary manifestations have been reported in celiac patients3-6 but little, if anything, is known about their mechanisms, even though the presence of a T lymphoid alveolitis had been described. One study has shown the presence of aberrant T cells in the lungs of some celiac patients.7 We confirm and extend these data by reporting here 7 patients with RCD II in whom the presence of specific aberrant T lymphocytes and clonal T-cell receptor gamma (TCR-g) rearrangements were detected in bronchoalveolar lavage (BAL), and/or in bronchial biopsies, or in mediastinal lymph nodes, all of which argue for the lung as an overt extradigestive site of the disease. All patients exhibited a massive digestive intraepithelial infiltration by cCD31, CD3–, CD4–, CD8–, and CD1031 T cells containing clonal TCR-g rearrangements associated in some way with the presence of similar T cells in skin and/or bone marrow (Table 1). Five of the 7 also exhibited the same phenotypically aberrant cells in BAL and/or bronchial biopsy T cells, accounting by fluorescenceactivated cell sorter analysis for 0.5% to 74% of total BAL lymphocytes. Lung cells also contained rearranged TCR-g T-cell clones, which were not always identical to those detected in the digestive mucosa and/or in blood. EATL developed in 4 of 7 patients. Two of them died of cutaneous lymphoma and 2 from digestive lymphoma.
Various clinical respiratory manifestations (chronic cough, hemoptysis, organized pneumonia) can occur in celiac patients, including the intrapulmonary location of RCD II–specific T cells in clinically asymptomatic patients.7 We confirm and extend the latter observation by showing the presence of clonal T cells in the lungs of 7 patients with RCD II in alveolar and/or bronchial epithelium or mediastinal lymph nodes. Interestingly, these clonal T-cells in some instances harbored different TCR-g rearrangements from those detected in the digestive mucosa or in circulating blood, ruling out their detection in the lung as mere blood contamination. Taken together, these data strongly argue for airway epithelium as an additional specific target of RCD II with its potentially most severe complication— aggressive local EATL. This should alert the clinicians in charge of such patients about the importance of including pulmonary evaluation in their routine workups. Indeed, these patients can be clinically and/or radiologically asymptomatic and yet exhibit abnormal T cells, with a potential for transformation into aggressive malignant cells. Jean Pastre´ Service de Pneumologie, Hopital ˆ Europeen ´ Georges Pompidou, Universite´ Paris Descartes, Paris, France Karine Juvin Service de Pneumologie, Hopital ˆ Europeen ´ Georges Pompidou, Universite´ Paris Descartes, Paris, France Georgia Malamut Service de Gastro-enterologie, ´ Hopital ˆ Europeen ´ Georges Pompidou, Universite´ Paris Descartes, Paris, France
Table 1. Characteristics of patients with refractory celiac disease type II and specific pulmonary involvement Age Patient Sex (years)
Aberrant T cells in digestive sample (%)*
Extradigestive localization of aberrant T cells
Aberrant T cells in BAL (%)*
Clonal TCR-g rearrangement in the lung
Site
Follow-up (months)
Outcome Died of digestive
1
F
36
60
Skin, bone marrow, lung
NA
1
BAL, BB
60
2
M
39
65
Bone marrow, lung
0.5
1
BAL
96
3
F
60
85
Bone marrow, lung
1
–
4
F
68
60
Skin, bone marrow, lung
0.5
1
5
F
51
80
Bone marrow, lung
1
6
F
57
70
Skin, bone marrow, blood,
7
F
31
40
Bone marrow, lung
lymphoma Alive
72
Alive
BAL
36
Died of skin
1
BAL, BB
36
Alive
74
1
BAL, BB
24
Died of skin
NA
1
Mediastinal
28
Died of digestive
lymphoma
lung
lymphoma lymph nodes
BB, bronchial biopsy; F, female; M, male; NA, not available. *Percentage of total sample lymphocytes.
lymphoma
From www.bloodjournal.org by guest on September 11, 2016. For personal use only. BLOOD, 5 JUNE 2014 x VOLUME 123, NUMBER 23
Coralie Derrieux Service d’Onco-hematologie ´ et Institut Necker Enfants Malades, INSERM U1151, Paris, France Christophe Cellier Service de Gastro-enterologie, ´ Hopital ˆ Europeen ´ Georges Pompidou, Universite´ Paris Descartes, Paris, France Dominique Israel-Biet ¨ Service de Pneumologie, Hopital ˆ Europeen ´ Georges Pompidou, Universite´ Paris Descartes, Paris, France Contribution: J.P. and K.J. collected and analyzed the data and participated in the writing of the manuscript; G.M. and C.C. provided all study patients and critically reviewed the manuscript; C.D. performed phenotypic and molecular studies; and D.I.-B. designed the study, wrote the manuscript and edited it. Conflict-of-interest disclosure: The authors declare no competing financial interests Correspondence: Dominique Israel-Biet, ¨ Universite´ Paris Descartes, Sorbonne Paris Cite, ´ Assistance Publique–Hopitaux de Paris, Service de Pneumologie, Hopital ˆ Europeen ´ Georges Pompidou, 20 rue Leblanc, 75015 Paris, France; e-mail: [email protected].
CORRESPONDENCE
3675
References 1. Malamut G, Meresse B, Cellier C, Cerf-Bensussan N. Refractory celiac disease: from bench to bedside. Semin Immunopathol. 2012;34(4):601-613. 2. Verbeek WH, von Blomberg BM, Coupe VM, Daum S, Mulder CJ, Schreurs MW. Aberrant T-lymphocytes in refractory coeliac disease are not strictly confined to a small intestinal intraepithelial localization. Cytometry B Clin Cytom. 2009;76(6): 367-374. 3. Tarlo SM, Broder I, Prokipchuk EJ, Peress L, Mintz S. Association between celiac disease and lung disease. Chest. 1981;80(6):715-718. 4. Bouros D, Panagou P, Rokkas T, Siafakas NM. Bronchoalveolar lavage findings in a young adult with idiopathic pulmonary haemosiderosis and coeliac disease. Eur Respir J. 1994;7(5):1009-1012. 5. Brightling CE, Symon FA, Birring SS, Wardlaw AJ, Robinson R, Pavord ID. A case of cough, lymphocytic bronchoalveolitis and coeliac disease with improvement following a gluten free diet. Thorax. 2002;57(1): 91-92. 6. Santos JW, Mello Neto AB, Marchiori RC, et al. Pulmonary hemosiderosis associated with celiac disease: improvement after a gluten-free diet. J Bras Pneumol. 2012;38(3):412-414. 7. Malamut G, Afchain P, Verkarre V, et al. Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology. 2009;136(1):81-90.
© 2014 by The American Society of Hematology
To the editor: ETV6 and signaling gene mutations are associated with secondary transformation of myelodysplastic syndromes to chronic myelomonocytic leukemia The genetic determinants that govern the phenotype associated with chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS) are unknown. Many recurrent mutations occur in both diseases, suggesting that the presence or absence of a solitary mutation is insufficient to drive specific phenotypes.1-3 Early expansion of clones harboring mutations associated with both diseases has been postulated as 1 driver of CMML.4 To dissect the genetic drivers of phenotype, we clinically and molecularly characterized a rare cohort of patients who presented as de novo MDS and transformed to secondary CMML.5 Cases that were identified in the MDS and CMML databases were manually reviewed to ensure that (1) all patients were diagnosed with World Health Organization-defined CMML; (2) all patients had MDS .6 weeks from the diagnosis of CMML; and (3) all patients had a monocyte count of ,1000/dL throughout the duration of MDS. Eighteen patients met criteria for secondary CMML, which accounted for 6.6% of the entire CMML cohort (n 5 270), with antecedent myeloid malignancies including MDS (n 5 13), MDS/ myeloproliferative neoplasms–unclassified (U) (n 5 4), and refractory anemia with ring sideroblasts and thrombocytosis (n 5 1). The median time to CMML transformation was 873 days (range, 230-1523), suggesting that the antecedent malignancy was stable and not an evolving CMML. Of the 18 secondary CMML cases, 4 had DNA at the time of CMML and 7 had DNA at the time of MDS and CMML from the same sample. We sequenced our index case at 2 time points for which the patient had clinically stable MDS and 2 time points after CMML transformation. A 26-gene amplicon-based targeted next-generation sequencing panel consisting of all known exons of genes previously identified to be recurrently mutated in CMML achieved an average read depth of 6523 on a Mi-Seq personal sequencer. After first pass analysis, sequencing data from sequential MDS time points 1 and 2
identified mutations in SETBP1, U2AF1, and RUNX1 at similar variant allele frequencies (VAFs), consistent with their clinical stability. Analysis of sequential CMML time points 3 and 4 identified the aforementioned mutations but also identified the acquisition of an ETV6 mutation at an increasing VAF that directly correlated with the emergence of monocytosis. Manual review of variant reads identified the ETV6 variant in the initial MDS sequential samples at frequencies of 3% and 4%, suggesting that this variant was present within a subclone at the time of MDS (Figure 1). Sequential samples in 6 other cases identified the acquisition of mutations in NRAS, CBL, and RUNX1 consistent with their role in CMML pathogenesis,6-8 as well as another case with ETV6 during first pass analysis. However, manual review of variant reads with sufficient depth identified that several variants were present at frequencies of #5%, suggesting that CMML transformation was associated with expansion of a preexisting MDS subclone. To our knowledge, this is the first report to molecularly characterize a secondary CMML cohort. Although genome-wide sequencing would annotate all genomic changes, our deep sequencing data demonstrate that longitudinal data analyses can generate important insights into molecular architecture during malignant transformation and provide insight into the genotype/phenotype of 2 related diseases. Eric Padron Department of Hematologic Malignancies, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, and the University of South Florida, Tampa, FL Sean Yoder Molecular Genomics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 123: 3674-3675 doi:10.1182/blood-2014-04-566513
Phenotypically aberrant clonal T cells in the lungs of patients with type II refractory celiac disease Jean Pastré, Karine Juvin, Georgia Malamut, Coralie Derrieux, Christophe Cellier and Dominique Israël-Biet
Updated information and services can be found at: http://www.bloodjournal.org/content/123/23/3674.full.html Articles on similar topics can be found in the following Blood collections Lymphoid Neoplasia (2370 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
BLOOD, 5 JUNE 2014 x VOLUME 123, NUMBER 23
CORRESPONDENCE
4. ENCODE Project Consortium. A user’s guide to the Encyclopedia of DNA Elements (ENCODE). PLoS Biol. 2011;9(4):e1001046. 5. Brune V, Tiacci E, Pfeil I, et al. Origin and pathogenesis of nodular lymphocytepredominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med. 2008;205(10):2251-2268. 6. Hall A, Karplus PA, Poole LB. Typical 2-Cys peroxiredoxins—structures, mechanisms and functions. FEBS J. 2009;276(9):2469-2477.
7. Giefing M, Winoto-Morbach S, Sosna J, et al. Hodgkin-Reed-Sternberg cells in classical Hodgkin lymphoma show alterations of genes encoding the NADPH oxidase complex and impaired reactive oxygen species synthesis capacity. PLoS ONE. 2013;8(12): e84928.
© 2014 by The American Society of Hematology
To the editor: Phenotypically aberrant clonal T cells in the lungs of patients with type II refractory celiac disease Type II refractory celiac disease (RCD II) is a rare condition characterized by a massive accumulation of intraepithelial lymphocytes with a natural killer/T phenotype and containing clonal T-cell rearrangements.1 Its severe prognosis is largely due to the development of an aggressive enteropathy-type–associated T-cell lymphoma (EATL). RCD II is a diffuse digestive but also extradigestive disease.2 Various pulmonary manifestations have been reported in celiac patients3-6 but little, if anything, is known about their mechanisms, even though the presence of a T lymphoid alveolitis had been described. One study has shown the presence of aberrant T cells in the lungs of some celiac patients.7 We confirm and extend these data by reporting here 7 patients with RCD II in whom the presence of specific aberrant T lymphocytes and clonal T-cell receptor gamma (TCR-g) rearrangements were detected in bronchoalveolar lavage (BAL), and/or in bronchial biopsies, or in mediastinal lymph nodes, all of which argue for the lung as an overt extradigestive site of the disease. All patients exhibited a massive digestive intraepithelial infiltration by cCD31, CD3–, CD4–, CD8–, and CD1031 T cells containing clonal TCR-g rearrangements associated in some way with the presence of similar T cells in skin and/or bone marrow (Table 1). Five of the 7 also exhibited the same phenotypically aberrant cells in BAL and/or bronchial biopsy T cells, accounting by fluorescenceactivated cell sorter analysis for 0.5% to 74% of total BAL lymphocytes. Lung cells also contained rearranged TCR-g T-cell clones, which were not always identical to those detected in the digestive mucosa and/or in blood. EATL developed in 4 of 7 patients. Two of them died of cutaneous lymphoma and 2 from digestive lymphoma.
Various clinical respiratory manifestations (chronic cough, hemoptysis, organized pneumonia) can occur in celiac patients, including the intrapulmonary location of RCD II–specific T cells in clinically asymptomatic patients.7 We confirm and extend the latter observation by showing the presence of clonal T cells in the lungs of 7 patients with RCD II in alveolar and/or bronchial epithelium or mediastinal lymph nodes. Interestingly, these clonal T-cells in some instances harbored different TCR-g rearrangements from those detected in the digestive mucosa or in circulating blood, ruling out their detection in the lung as mere blood contamination. Taken together, these data strongly argue for airway epithelium as an additional specific target of RCD II with its potentially most severe complication— aggressive local EATL. This should alert the clinicians in charge of such patients about the importance of including pulmonary evaluation in their routine workups. Indeed, these patients can be clinically and/or radiologically asymptomatic and yet exhibit abnormal T cells, with a potential for transformation into aggressive malignant cells. Jean Pastre´ Service de Pneumologie, Hopital ˆ Europeen ´ Georges Pompidou, Universite´ Paris Descartes, Paris, France Karine Juvin Service de Pneumologie, Hopital ˆ Europeen ´ Georges Pompidou, Universite´ Paris Descartes, Paris, France Georgia Malamut Service de Gastro-enterologie, ´ Hopital ˆ Europeen ´ Georges Pompidou, Universite´ Paris Descartes, Paris, France
Table 1. Characteristics of patients with refractory celiac disease type II and specific pulmonary involvement Age Patient Sex (years)
Aberrant T cells in digestive sample (%)*
Extradigestive localization of aberrant T cells
Aberrant T cells in BAL (%)*
Clonal TCR-g rearrangement in the lung
Site
Follow-up (months)
Outcome Died of digestive
1
F
36
60
Skin, bone marrow, lung
NA
1
BAL, BB
60
2
M
39
65
Bone marrow, lung
0.5
1
BAL
96
3
F
60
85
Bone marrow, lung
1
–
4
F
68
60
Skin, bone marrow, lung
0.5
1
5
F
51
80
Bone marrow, lung
1
6
F
57
70
Skin, bone marrow, blood,
7
F
31
40
Bone marrow, lung
lymphoma Alive
72
Alive
BAL
36
Died of skin
1
BAL, BB
36
Alive
74
1
BAL, BB
24
Died of skin
NA
1
Mediastinal
28
Died of digestive
lymphoma
lung
lymphoma lymph nodes
BB, bronchial biopsy; F, female; M, male; NA, not available. *Percentage of total sample lymphocytes.
lymphoma
From www.bloodjournal.org by guest on September 11, 2016. For personal use only. BLOOD, 5 JUNE 2014 x VOLUME 123, NUMBER 23
Coralie Derrieux Service d’Onco-hematologie ´ et Institut Necker Enfants Malades, INSERM U1151, Paris, France Christophe Cellier Service de Gastro-enterologie, ´ Hopital ˆ Europeen ´ Georges Pompidou, Universite´ Paris Descartes, Paris, France Dominique Israel-Biet ¨ Service de Pneumologie, Hopital ˆ Europeen ´ Georges Pompidou, Universite´ Paris Descartes, Paris, France Contribution: J.P. and K.J. collected and analyzed the data and participated in the writing of the manuscript; G.M. and C.C. provided all study patients and critically reviewed the manuscript; C.D. performed phenotypic and molecular studies; and D.I.-B. designed the study, wrote the manuscript and edited it. Conflict-of-interest disclosure: The authors declare no competing financial interests Correspondence: Dominique Israel-Biet, ¨ Universite´ Paris Descartes, Sorbonne Paris Cite, ´ Assistance Publique–Hopitaux de Paris, Service de Pneumologie, Hopital ˆ Europeen ´ Georges Pompidou, 20 rue Leblanc, 75015 Paris, France; e-mail: [email protected].
CORRESPONDENCE
3675
References 1. Malamut G, Meresse B, Cellier C, Cerf-Bensussan N. Refractory celiac disease: from bench to bedside. Semin Immunopathol. 2012;34(4):601-613. 2. Verbeek WH, von Blomberg BM, Coupe VM, Daum S, Mulder CJ, Schreurs MW. Aberrant T-lymphocytes in refractory coeliac disease are not strictly confined to a small intestinal intraepithelial localization. Cytometry B Clin Cytom. 2009;76(6): 367-374. 3. Tarlo SM, Broder I, Prokipchuk EJ, Peress L, Mintz S. Association between celiac disease and lung disease. Chest. 1981;80(6):715-718. 4. Bouros D, Panagou P, Rokkas T, Siafakas NM. Bronchoalveolar lavage findings in a young adult with idiopathic pulmonary haemosiderosis and coeliac disease. Eur Respir J. 1994;7(5):1009-1012. 5. Brightling CE, Symon FA, Birring SS, Wardlaw AJ, Robinson R, Pavord ID. A case of cough, lymphocytic bronchoalveolitis and coeliac disease with improvement following a gluten free diet. Thorax. 2002;57(1): 91-92. 6. Santos JW, Mello Neto AB, Marchiori RC, et al. Pulmonary hemosiderosis associated with celiac disease: improvement after a gluten-free diet. J Bras Pneumol. 2012;38(3):412-414. 7. Malamut G, Afchain P, Verkarre V, et al. Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology. 2009;136(1):81-90.
© 2014 by The American Society of Hematology
To the editor: ETV6 and signaling gene mutations are associated with secondary transformation of myelodysplastic syndromes to chronic myelomonocytic leukemia The genetic determinants that govern the phenotype associated with chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS) are unknown. Many recurrent mutations occur in both diseases, suggesting that the presence or absence of a solitary mutation is insufficient to drive specific phenotypes.1-3 Early expansion of clones harboring mutations associated with both diseases has been postulated as 1 driver of CMML.4 To dissect the genetic drivers of phenotype, we clinically and molecularly characterized a rare cohort of patients who presented as de novo MDS and transformed to secondary CMML.5 Cases that were identified in the MDS and CMML databases were manually reviewed to ensure that (1) all patients were diagnosed with World Health Organization-defined CMML; (2) all patients had MDS .6 weeks from the diagnosis of CMML; and (3) all patients had a monocyte count of ,1000/dL throughout the duration of MDS. Eighteen patients met criteria for secondary CMML, which accounted for 6.6% of the entire CMML cohort (n 5 270), with antecedent myeloid malignancies including MDS (n 5 13), MDS/ myeloproliferative neoplasms–unclassified (U) (n 5 4), and refractory anemia with ring sideroblasts and thrombocytosis (n 5 1). The median time to CMML transformation was 873 days (range, 230-1523), suggesting that the antecedent malignancy was stable and not an evolving CMML. Of the 18 secondary CMML cases, 4 had DNA at the time of CMML and 7 had DNA at the time of MDS and CMML from the same sample. We sequenced our index case at 2 time points for which the patient had clinically stable MDS and 2 time points after CMML transformation. A 26-gene amplicon-based targeted next-generation sequencing panel consisting of all known exons of genes previously identified to be recurrently mutated in CMML achieved an average read depth of 6523 on a Mi-Seq personal sequencer. After first pass analysis, sequencing data from sequential MDS time points 1 and 2
identified mutations in SETBP1, U2AF1, and RUNX1 at similar variant allele frequencies (VAFs), consistent with their clinical stability. Analysis of sequential CMML time points 3 and 4 identified the aforementioned mutations but also identified the acquisition of an ETV6 mutation at an increasing VAF that directly correlated with the emergence of monocytosis. Manual review of variant reads identified the ETV6 variant in the initial MDS sequential samples at frequencies of 3% and 4%, suggesting that this variant was present within a subclone at the time of MDS (Figure 1). Sequential samples in 6 other cases identified the acquisition of mutations in NRAS, CBL, and RUNX1 consistent with their role in CMML pathogenesis,6-8 as well as another case with ETV6 during first pass analysis. However, manual review of variant reads with sufficient depth identified that several variants were present at frequencies of #5%, suggesting that CMML transformation was associated with expansion of a preexisting MDS subclone. To our knowledge, this is the first report to molecularly characterize a secondary CMML cohort. Although genome-wide sequencing would annotate all genomic changes, our deep sequencing data demonstrate that longitudinal data analyses can generate important insights into molecular architecture during malignant transformation and provide insight into the genotype/phenotype of 2 related diseases. Eric Padron Department of Hematologic Malignancies, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, and the University of South Florida, Tampa, FL Sean Yoder Molecular Genomics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 123: 3674-3675 doi:10.1182/blood-2014-04-566513
Phenotypically aberrant clonal T cells in the lungs of patients with type II refractory celiac disease Jean Pastré, Karine Juvin, Georgia Malamut, Coralie Derrieux, Christophe Cellier and Dominique Israël-Biet
Updated information and services can be found at: http://www.bloodjournal.org/content/123/23/3674.full.html Articles on similar topics can be found in the following Blood collections Lymphoid Neoplasia (2370 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
