From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
adverse prognostic implications of FLT3-ITD, although the role of HSCT, specifically in those with high ITD-AR, was not established.2,6-8 Recent trials have incorporated diagnostic FLT3-ITD in risk-based therapy allocation, where those with FLT3-ITD, especially those with high ITD-AR, are allocated to the highrisk therapeutic arm and receive HSCT in first CR from the most suitable donors.9 The article by Schlenk et al has adequate power to evaluate the efficacy of HSCT in those with high ITD-AR.1 They demonstrate that those with high ITD-AR, where FLT3-ITD is the dominant lesion, benefit from HSCT, whereas those with low AR (alternate dominant mutation) show no such benefit, and clinically behave similarly to those without FLT3-ITD. It also highlights the fact that leukemic cells with FLT3-ITD may be especially susceptible to the allogeneic effect of the HSCT and allocation of patients with FLT3-ITD patients to HSCT must be more precise and be based on the ITD mutation load and not on the mere presence of the mutation with low AR. Further, one must keep in mind that any prognostic factor is highly dependent on the therapeutic intervention, and the significance of prognostic biomarkers may change with changing therapies. One example is the recent data that patients with FLT3-ITD who received gemtuzumab ozogamicin (GO) may have a more favorable outcome.9,10 This observed improvement in outcome with GO raises the caveat that prognostic significance of FLT3-ITD and ITD-AR in patients treated with GO should be evaluated separately from the non-GO recipients. Although the mechanism by which GO mediates improved outcome in patients with FLT3-ITD is not known, it is possible that enhanced response to GO and improved outcome with HSCT may provide therapeutic options in addition to, and in combination with, tyrosine kinase inhibitors and may provide viable targeted options in this select cohort of patients. Further, as those with low ITD-AR behave as FLT3/WT, perhaps only those with high ITD-AR should be targeted for such FLT3-ITD–directed therapies. Conflict-of-interest disclosure: The author declares no competing financial interests n REFERENCES 1. Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD–positive AML with respect to allogeneic transplantation. Blood. 2014;124(23):3441-3449.
3342
2. Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. 2006;108(12):3654-3661. 3. Stirewalt DL, Pogosova-Agadjanyan EL, Tsuchiya K, Joaquin J, Meshinchi S. Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ ITD AML. Blood Cancer J. 2014;4:e208. 4. Allen C, Hills RK, Lamb K, et al. The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia. Leukemia. 2013;27(9):1891-1901. 5. Meshinchi S, Ries RE, Trevino LR, et al. Identification of novel somatic mutations, regions of recurrent loss of heterozygosity (LOH), and significant clonal evolution from diagnosis to relapse in childhood AML determined by exome capture sequencing: an NCI/COG target AML study. ASH Annu Mtg Abstr. 2012;120(21):123. 6. Schlenk RF, D¨ohner K, Krauter J, et al; GermanAustrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008; 358(18):1909-1918.
7. Schlenk R, Krauter J, Fr¨ohling S, et al. Postremission therapy with an allogeneic transplantation from an HLAmatched family donor seems to overcome the negative prognostic impact of FLT3-ITD in younger patients with acute myeloid leukemia exhibiting a normal karyotype. Blood. 2005;106(11):2353. 8. Meshinchi S, Arceci RJ, Sanders JE, et al. Role of allogeneic stem cell transplantation in FLT3/ITD-positive AML. Blood. 2006;108(1):400, author reply 400-401. 9. Gamis AS, Alonzo TA, Meshinchi S, et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group Trial AAML0531 [published online ahead of print August 4, 2014]. J Clin Oncol. pii:JCO.2014.55.3628. 10. Renneville A, Abdelali RB, Chevret S, et al. Clinical impact of gene mutations and lesions detected by SNParray karyotyping in acute myeloid leukemia patients in the context of gemtuzumab ozogamicin treatment: results of the ALFA-0701 trial. Oncotarget. 2014;5(4):916-932. © 2014 by The American Society of Hematology
l l l RED CELLS, IRON, & ERYTHROPOIESIS
Comment on Rug et al, page 3459
A traffic jam to reduce morbidity in malaria ----------------------------------------------------------------------------------------------------Hans-Peter Beck
SWISS TROPICAL AND PUBLIC HEALTH INSTITUTE; UNIVERSITY OF BASEL
In this issue of Blood, Rug et al report that genetic disruption of a single malaria parasite protein disturbs recruitment of host actin and protein trafficking, thus disabling parasite adherence to the host endothelial lining, which is the major cause of malaria pathology.1
M
alaria caused by Plasmodium falciparum still elicits a substantial burden of disease mainly in sub-Saharan countries, where malaria is still endemic despite many efforts to curb the disease. P falciparum is an aggressive invader of cells, beginning with the invasion of hepatocytes upon the infectious bite of an Anopheles mosquito. Subsequently, after a massive cellular amplification, the P falciparum blood forms emerge and invade mature erythrocytes. These blood forms can cause severe anemia, but the true damages inflicted by this deadly disease come from structural modifications of the infected erythrocyte caused by the parasite. It has long been known that the parasite exports a massive number of proteins into the host cell cytosol and beyond, but there has been little evidence of how this works (see figure). In their paper, Rug and colleagues1 share information on the function of exported proteins of P falciparum and
their involvement in the remodeling of the host cell. Why is this important? Parasite-induced modifications change the form and shape of the infected erythrocyte; they also change both the osmotic regulation of the host cell and the membrane rigidity. Most importantly, the induced modifications convey the ability of infected erythrocytes to adhere to the endothelial lining of the capillaries.2 Most of this adherence is mediated by a single parasite protein called P falciparum erythrocyte membrane protein 1 (PfEMP1). This molecule, encoded by a variable parasite gene family, is embedded into the erythrocyte membrane and conveys adherence to a variety of endothelial receptors.2 This cytoadherence protects the parasite from splenic clearance and is considered the major virulence factor in malaria tropica. Therefore, understanding how PfEMP1 migrates to the surface of the infected cell is extremely important and may lead to
BLOOD, 27 NOVEMBER 2014 x VOLUME 124, NUMBER 23
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
trafficking was impaired.9 This difference raises the question of whether there are different mechanisms and pathways of translocation. In conclusion, the paper by Rug and colleagues provides a further piece to the puzzle and augments our understanding of how P falciparum modifies the host erythrocyte upon infection to permit its intracellular survival. The authors provide fair evidence of vesicular transport to and from the parasitederived Maurer’s clefts, show convincingly how the parasite overtakes host proteins, and show clearly that genetic disruption of a single protein (here PfPTP1) results in a loss of surface-exposed PfEMP1 and STEVOR. The similarity between phenotypes of a host genetic trait (sickle cell anemia) and a genetic disruption of a single parasite gene (PfPTP1) is striking, both with disrupted Maurer’s clefts and with completely disorganized actin filaments essential for PfEMP1 translocation. These findings should engage us to think about new approaches to inhibit these processes in our endeavors to develop innovative strategies to eliminate malaria. The author declares no competing financial interests. n Cellular modifications occurring during parasite growth in the host erythrocyte and confirmed locations of exported proteins within the export network. The location of PfPTP1 is indicated by red arrows. Figure modified with permission from Mundwiler-Pachlatko and Beck.10
innovative interventions that help to eliminate the parasite and reduce morbidity in infected persons. Previously, parts of the export machinery had already been identified, starting from an export signal called PEXEL,3 followed by the discovery of a translocon complex that transports proteins to be exported through the parasitophorous vacuolar membrane.4 This subsequently led to the identification of a small number of proteins that seemed to be essential for PfEMP1 translocation to the cell surface.5 One that had been identified in a genetic screen was PfEMP1 trafficking protein 1 (PfPTP1), which the current manuscript convincingly shows is essential for this translocation.1 The essentiality of a number of proteins for PfEMP1 translocation has been demonstrated previously5-7; however, in this manuscript, the authors not only show that parasitederived structures known as Maurer’s clefts are completely distorted but that recruitment of host proteins is also disturbed. It is fascinating to see how the parasite not only modifies the cell by its own proteins but how it overtakes essential host-cell proteins such as actin for the transport of vesicles to the host-cell surface. The first indications of the importance of
correctly assembled actin filaments were seen in studies using P falciparum–infected hemoglobin S host cells, in which Cyrklaff and colleagues elegantly demonstrated that actin filaments were incorrectly assembled. This prevented vesicles, apparently transporting PfEMP1, to move to the erythrocyte membrane.8 These findings provide a sound explanation for why the sickle cell trait protects against severe malaria. Rug et al mimic a similar phenotype with the genetic disruption of PfPTP1, and it must be assumed that, similar to sickle cells, these parasite-infected cells can no longer bind to endothelial receptors. Interestingly, PfPTP1 knockout parasites also showed an impaired transport of a second ligand called STEVOR, which has been implicated in a process called rosetting, in which infected erythrocytes bind to noninfected red blood cells. STEVOR was also no longer translocated in the PfPTP1 knockout parasites, indicating that this dangerous phenomenon would also be eliminated. This is in contrast to findings from a genetic deletion of MAHRP1, another Maurer’s cleft protein also essential for PfEMP1 translocation,7 where only PfEMP1
BLOOD, 27 NOVEMBER 2014 x VOLUME 124, NUMBER 23
REFERENCES 1. Rug M, Cyrklaff M, Mikkonen A, et al. Export of virulence proteins by malaria-infected erythrocytes involves remodeling of host actin cytoskeleton. Blood. 2014;124(23):3459-3468. 2. Kyes S, Horrocks P, Newbold C. Antigenic variation at the infected red cell surface in malaria. Annu Rev Microbiol. 2001;55:673-707. 3. Marti M, Good RT, Rug M, Knuepfer E, Cowman AF. Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science. 2004;306(5703):1930-1933. 4. de Koning-Ward TF, Gilson PR, Boddey JA, et al. A newly discovered protein export machine in malaria parasites. Nature. 2009;459(7249):945-949. 5. Maier AG, Rug M, O’Neill MT, et al. Exported proteins required for virulence and rigidity of Plasmodium falciparuminfected human erythrocytes. Cell. 2008;134(1):48-61. 6. Cooke BM, Buckingham DW, Glenister FK, et al. A Maurer’s cleft-associated protein is essential for expression of the major malaria virulence antigen on the surface of infected red blood cells. J Cell Biol. 2006;172(6):899-908. 7. Spycher C, Rug M, Pachlatko E, et al. The Maurer’s cleft protein MAHRP1 is essential for trafficking of PfEMP1 to the surface of Plasmodium falciparum-infected erythrocytes. Mol Microbiol. 2008;68(5):1300-1314. 8. Cyrklaff M, Sanchez CP, Frischknecht F, Lanzer M. Host actin remodeling and protection from malaria by hemoglobinopathies. Trends Parasitol. 2012;28(11):479-485. 9. Niang M, Bei AK, Madnani KG, et al. STEVOR is a Plasmodium falciparum erythrocyte binding protein that mediates merozoite invasion and rosetting. Cell Host Microbe. 2014;16(1):81-93. 10. Mundwiler-Pachlatko E, Beck HP. Maurer’s clefts, the enigma of Plasmodium falciparum. Proc Natl Acad Sci USA. 2013;110(50):19987-19994.
© 2014 by The American Society of Hematology
3343
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 124: 3342-3343 doi:10.1182/blood-2014-09-597740
A traffic jam to reduce morbidity in malaria Hans-Peter Beck
Updated information and services can be found at: http://www.bloodjournal.org/content/124/23/3342.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 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.
adverse prognostic implications of FLT3-ITD, although the role of HSCT, specifically in those with high ITD-AR, was not established.2,6-8 Recent trials have incorporated diagnostic FLT3-ITD in risk-based therapy allocation, where those with FLT3-ITD, especially those with high ITD-AR, are allocated to the highrisk therapeutic arm and receive HSCT in first CR from the most suitable donors.9 The article by Schlenk et al has adequate power to evaluate the efficacy of HSCT in those with high ITD-AR.1 They demonstrate that those with high ITD-AR, where FLT3-ITD is the dominant lesion, benefit from HSCT, whereas those with low AR (alternate dominant mutation) show no such benefit, and clinically behave similarly to those without FLT3-ITD. It also highlights the fact that leukemic cells with FLT3-ITD may be especially susceptible to the allogeneic effect of the HSCT and allocation of patients with FLT3-ITD patients to HSCT must be more precise and be based on the ITD mutation load and not on the mere presence of the mutation with low AR. Further, one must keep in mind that any prognostic factor is highly dependent on the therapeutic intervention, and the significance of prognostic biomarkers may change with changing therapies. One example is the recent data that patients with FLT3-ITD who received gemtuzumab ozogamicin (GO) may have a more favorable outcome.9,10 This observed improvement in outcome with GO raises the caveat that prognostic significance of FLT3-ITD and ITD-AR in patients treated with GO should be evaluated separately from the non-GO recipients. Although the mechanism by which GO mediates improved outcome in patients with FLT3-ITD is not known, it is possible that enhanced response to GO and improved outcome with HSCT may provide therapeutic options in addition to, and in combination with, tyrosine kinase inhibitors and may provide viable targeted options in this select cohort of patients. Further, as those with low ITD-AR behave as FLT3/WT, perhaps only those with high ITD-AR should be targeted for such FLT3-ITD–directed therapies. Conflict-of-interest disclosure: The author declares no competing financial interests n REFERENCES 1. Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD–positive AML with respect to allogeneic transplantation. Blood. 2014;124(23):3441-3449.
3342
2. Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. 2006;108(12):3654-3661. 3. Stirewalt DL, Pogosova-Agadjanyan EL, Tsuchiya K, Joaquin J, Meshinchi S. Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ ITD AML. Blood Cancer J. 2014;4:e208. 4. Allen C, Hills RK, Lamb K, et al. The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia. Leukemia. 2013;27(9):1891-1901. 5. Meshinchi S, Ries RE, Trevino LR, et al. Identification of novel somatic mutations, regions of recurrent loss of heterozygosity (LOH), and significant clonal evolution from diagnosis to relapse in childhood AML determined by exome capture sequencing: an NCI/COG target AML study. ASH Annu Mtg Abstr. 2012;120(21):123. 6. Schlenk RF, D¨ohner K, Krauter J, et al; GermanAustrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008; 358(18):1909-1918.
7. Schlenk R, Krauter J, Fr¨ohling S, et al. Postremission therapy with an allogeneic transplantation from an HLAmatched family donor seems to overcome the negative prognostic impact of FLT3-ITD in younger patients with acute myeloid leukemia exhibiting a normal karyotype. Blood. 2005;106(11):2353. 8. Meshinchi S, Arceci RJ, Sanders JE, et al. Role of allogeneic stem cell transplantation in FLT3/ITD-positive AML. Blood. 2006;108(1):400, author reply 400-401. 9. Gamis AS, Alonzo TA, Meshinchi S, et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group Trial AAML0531 [published online ahead of print August 4, 2014]. J Clin Oncol. pii:JCO.2014.55.3628. 10. Renneville A, Abdelali RB, Chevret S, et al. Clinical impact of gene mutations and lesions detected by SNParray karyotyping in acute myeloid leukemia patients in the context of gemtuzumab ozogamicin treatment: results of the ALFA-0701 trial. Oncotarget. 2014;5(4):916-932. © 2014 by The American Society of Hematology
l l l RED CELLS, IRON, & ERYTHROPOIESIS
Comment on Rug et al, page 3459
A traffic jam to reduce morbidity in malaria ----------------------------------------------------------------------------------------------------Hans-Peter Beck
SWISS TROPICAL AND PUBLIC HEALTH INSTITUTE; UNIVERSITY OF BASEL
In this issue of Blood, Rug et al report that genetic disruption of a single malaria parasite protein disturbs recruitment of host actin and protein trafficking, thus disabling parasite adherence to the host endothelial lining, which is the major cause of malaria pathology.1
M
alaria caused by Plasmodium falciparum still elicits a substantial burden of disease mainly in sub-Saharan countries, where malaria is still endemic despite many efforts to curb the disease. P falciparum is an aggressive invader of cells, beginning with the invasion of hepatocytes upon the infectious bite of an Anopheles mosquito. Subsequently, after a massive cellular amplification, the P falciparum blood forms emerge and invade mature erythrocytes. These blood forms can cause severe anemia, but the true damages inflicted by this deadly disease come from structural modifications of the infected erythrocyte caused by the parasite. It has long been known that the parasite exports a massive number of proteins into the host cell cytosol and beyond, but there has been little evidence of how this works (see figure). In their paper, Rug and colleagues1 share information on the function of exported proteins of P falciparum and
their involvement in the remodeling of the host cell. Why is this important? Parasite-induced modifications change the form and shape of the infected erythrocyte; they also change both the osmotic regulation of the host cell and the membrane rigidity. Most importantly, the induced modifications convey the ability of infected erythrocytes to adhere to the endothelial lining of the capillaries.2 Most of this adherence is mediated by a single parasite protein called P falciparum erythrocyte membrane protein 1 (PfEMP1). This molecule, encoded by a variable parasite gene family, is embedded into the erythrocyte membrane and conveys adherence to a variety of endothelial receptors.2 This cytoadherence protects the parasite from splenic clearance and is considered the major virulence factor in malaria tropica. Therefore, understanding how PfEMP1 migrates to the surface of the infected cell is extremely important and may lead to
BLOOD, 27 NOVEMBER 2014 x VOLUME 124, NUMBER 23
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
trafficking was impaired.9 This difference raises the question of whether there are different mechanisms and pathways of translocation. In conclusion, the paper by Rug and colleagues provides a further piece to the puzzle and augments our understanding of how P falciparum modifies the host erythrocyte upon infection to permit its intracellular survival. The authors provide fair evidence of vesicular transport to and from the parasitederived Maurer’s clefts, show convincingly how the parasite overtakes host proteins, and show clearly that genetic disruption of a single protein (here PfPTP1) results in a loss of surface-exposed PfEMP1 and STEVOR. The similarity between phenotypes of a host genetic trait (sickle cell anemia) and a genetic disruption of a single parasite gene (PfPTP1) is striking, both with disrupted Maurer’s clefts and with completely disorganized actin filaments essential for PfEMP1 translocation. These findings should engage us to think about new approaches to inhibit these processes in our endeavors to develop innovative strategies to eliminate malaria. The author declares no competing financial interests. n Cellular modifications occurring during parasite growth in the host erythrocyte and confirmed locations of exported proteins within the export network. The location of PfPTP1 is indicated by red arrows. Figure modified with permission from Mundwiler-Pachlatko and Beck.10
innovative interventions that help to eliminate the parasite and reduce morbidity in infected persons. Previously, parts of the export machinery had already been identified, starting from an export signal called PEXEL,3 followed by the discovery of a translocon complex that transports proteins to be exported through the parasitophorous vacuolar membrane.4 This subsequently led to the identification of a small number of proteins that seemed to be essential for PfEMP1 translocation to the cell surface.5 One that had been identified in a genetic screen was PfEMP1 trafficking protein 1 (PfPTP1), which the current manuscript convincingly shows is essential for this translocation.1 The essentiality of a number of proteins for PfEMP1 translocation has been demonstrated previously5-7; however, in this manuscript, the authors not only show that parasitederived structures known as Maurer’s clefts are completely distorted but that recruitment of host proteins is also disturbed. It is fascinating to see how the parasite not only modifies the cell by its own proteins but how it overtakes essential host-cell proteins such as actin for the transport of vesicles to the host-cell surface. The first indications of the importance of
correctly assembled actin filaments were seen in studies using P falciparum–infected hemoglobin S host cells, in which Cyrklaff and colleagues elegantly demonstrated that actin filaments were incorrectly assembled. This prevented vesicles, apparently transporting PfEMP1, to move to the erythrocyte membrane.8 These findings provide a sound explanation for why the sickle cell trait protects against severe malaria. Rug et al mimic a similar phenotype with the genetic disruption of PfPTP1, and it must be assumed that, similar to sickle cells, these parasite-infected cells can no longer bind to endothelial receptors. Interestingly, PfPTP1 knockout parasites also showed an impaired transport of a second ligand called STEVOR, which has been implicated in a process called rosetting, in which infected erythrocytes bind to noninfected red blood cells. STEVOR was also no longer translocated in the PfPTP1 knockout parasites, indicating that this dangerous phenomenon would also be eliminated. This is in contrast to findings from a genetic deletion of MAHRP1, another Maurer’s cleft protein also essential for PfEMP1 translocation,7 where only PfEMP1
BLOOD, 27 NOVEMBER 2014 x VOLUME 124, NUMBER 23
REFERENCES 1. Rug M, Cyrklaff M, Mikkonen A, et al. Export of virulence proteins by malaria-infected erythrocytes involves remodeling of host actin cytoskeleton. Blood. 2014;124(23):3459-3468. 2. Kyes S, Horrocks P, Newbold C. Antigenic variation at the infected red cell surface in malaria. Annu Rev Microbiol. 2001;55:673-707. 3. Marti M, Good RT, Rug M, Knuepfer E, Cowman AF. Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science. 2004;306(5703):1930-1933. 4. de Koning-Ward TF, Gilson PR, Boddey JA, et al. A newly discovered protein export machine in malaria parasites. Nature. 2009;459(7249):945-949. 5. Maier AG, Rug M, O’Neill MT, et al. Exported proteins required for virulence and rigidity of Plasmodium falciparuminfected human erythrocytes. Cell. 2008;134(1):48-61. 6. Cooke BM, Buckingham DW, Glenister FK, et al. A Maurer’s cleft-associated protein is essential for expression of the major malaria virulence antigen on the surface of infected red blood cells. J Cell Biol. 2006;172(6):899-908. 7. Spycher C, Rug M, Pachlatko E, et al. The Maurer’s cleft protein MAHRP1 is essential for trafficking of PfEMP1 to the surface of Plasmodium falciparum-infected erythrocytes. Mol Microbiol. 2008;68(5):1300-1314. 8. Cyrklaff M, Sanchez CP, Frischknecht F, Lanzer M. Host actin remodeling and protection from malaria by hemoglobinopathies. Trends Parasitol. 2012;28(11):479-485. 9. Niang M, Bei AK, Madnani KG, et al. STEVOR is a Plasmodium falciparum erythrocyte binding protein that mediates merozoite invasion and rosetting. Cell Host Microbe. 2014;16(1):81-93. 10. Mundwiler-Pachlatko E, Beck HP. Maurer’s clefts, the enigma of Plasmodium falciparum. Proc Natl Acad Sci USA. 2013;110(50):19987-19994.
© 2014 by The American Society of Hematology
3343
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 124: 3342-3343 doi:10.1182/blood-2014-09-597740
A traffic jam to reduce morbidity in malaria Hans-Peter Beck
Updated information and services can be found at: http://www.bloodjournal.org/content/124/23/3342.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 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.
