From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
REFERENCES 1. van Keimpema M, Gruneberg ¨ LJ, Mokry M, et al. FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-kB to promote survival of human B cells. Blood. 2014;124(23):3431-3440.
open-label, phase 2 study [abstract]. Blood. 2012;120(21). Abstract 686. 6. Yang Y, Shaffer AL III, Emre NC, et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell. 2012;21(6):723-737.
2. Abramson JS, Zelenetz AD. Recent advances in the treatment of non-Hodgkin’s lymphomas. J Natl Compr Canc Netw. 2013;11(5 suppl):671-675.
7. Katoh M, Igarashi M, Fukuda H, Nakagama H, Katoh M. Cancer genetics and genomics of human FOX family genes. Cancer Lett. 2013;328(2):198-206.
3. Zelenetz AD, Wierda WG, Abramson JS, et al; National Comprehensive Cancer Network. Non-Hodgkin’s lymphomas, version 1.2013. J Natl Compr Canc Netw. 2013;11(3):257-272, quiz 273.
8. Banham AH, Connors JM, Brown PJ, et al. Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma. Clin Cancer Res. 2005;11(3):1065-1072.
4. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503-511. 5. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (pci-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter,
9. Sagaert X, de Paepe P, Libbrecht L, et al. Forkhead box protein P1 expression in mucosa-associated lymphoid tissue lymphomas predicts poor prognosis and transformation to diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(16):2490-2497. © 2014 by The American Society of Hematology
l l l MYELOID NEOPLASIA
Comment on Schlenk et al, page 3441
Allelic ratio: a marker of clonal dominance ----------------------------------------------------------------------------------------------------Soheil Meshinchi
FRED HUTCHINSON CANCER RESEARCH INSTITUTE
In this issue of Blood, Schlenk et al provide compelling data on the prognostic implications of FMS-like tyrosine kinase 3 (FLT3)/internal tandem duplication allelic ratio (ITD-AR), as well as its impact on response to allogeneic stem cell transplantation.1
T
hey provide detailed analysis of data from a large cohort of patients with FLT3-ITD treated in 4 multicenter German-Austrian Acute Myeloid Leukemia (AML) Study Group (AMLSG) trials and correlate the variation in ITD-AR with response to induction chemotherapy and clinical outcome. Given the significant variation in ITD-AR and lack of a preestablished biological threshold, the authors establish a statistically defined cut-point for clinically meaningful ITD-AR of 0.51 for further correlation with clinical outcome. It is important to note that this ITD-AR is similar to those previously defined clinically defined thresholds.2 They demonstrate that those with high ITD-AR have a significantly worse complete remission (CR) rate and correspondingly poor survival and relapse. They further demonstrate that the adverse outcome of high ITD-AR is abrogated by stem cell transplantation. In contrast to patients with high ITD-AR, there appears to be no distinction between
those with low ITD-AR and those without FLT3-ITD (FLT3 wild type [FLT3/WT]) in terms of overall outcome or response to hematopoietic stem cell transplantation (HSCT). To discuss the role of varying ITD-AR in AML, one must address the underlying mechanism for such a wide variation in AR (ranging from 0.01 to .100), which is the ultimate representation of the enormous complexity and genomic heterogeneity of FLT3-ITD–positive AML, as multiple factors contribute to this variation in ITD-AR. The most obvious of these factors is that ITD-AR is a representation of the state of clonal dominance (or lack thereof) of the mutation, where in those with high ITD-AR, FLT3-ITD is the dominant lesion and is present in the majority or all of the leukemic cells. In contrast, in those with low ITD-AR, FLT3-ITD is present in a minor subclone within the bulk leukemic population. Single cell genotyping of leukemic cells from patients with varying ITD-AR established
BLOOD, 27 NOVEMBER 2014 x VOLUME 124, NUMBER 23
the genomic heterogeneity in FLT3-ITD AML, demonstrating that FLT3-ITD may be present in a major (high ITD-AR) or minor (low ITD-AR) subset of leukemic cells, and defined an association of ITD-AR with the proportion of individual cells that harbor FLT3-ITD and contribute to the final ITD-AR value.3 ITD-AR is further impacted by the associated copy-neutral loss of heterozygosity (LOH) of chromosome 13q (13q CN-LOH) in patients with FLT3-ITD. This genomic variant is the result of a homologous recombination-mediated process where the WT allele is replaced by the allele with FLT3-ITD, resulting in loss of heterozygosity (without copy number loss), leading to evolution of homozygous ITD. Single cell genotyping further demonstrated that in patients with FLT3-ITD, leukemic cells are composed of a mixture of homozygous FLT3-ITD, heterozygous FLT3-ITD, and FLT3/WT, with a final value of ITD-AR determined by the proportion of each genotypic subset.3 The fact that 13q CN-LOH is uniquely observed in the setting of FLT3-ITD may suggest a causal association between FLT3-ITD and evolution of this unique genomic event. Ultimately, ITD-AR represents the extent of the clonal dominance of FLT3-ITD (with contribution of 13q CN-LOH), where in those with high ITD-AR, FLT3-ITD is present in the majority of the leukemic cells and likely the dominant and driving genomic event. In contrast, in those with low ITD-AR, where FLT3-ITD is present in the minority of leukemic cells, FLT3-ITD is unlikely to be the driving event and contribute to leukemic relapse. The clinical impact of AR has been observed in other mutations by demonstration of the association of the AR of KIT and CBL mutations with outcome.4 These data suggest that we may need to alter our approach to evaluation of diagnostic mutations in AML and determine not only what the mutation is, but whether the mutation is a dominant, driving lesion or a minor variant. An additional layer of data that substantiates the significance of mutation burden at diagnosis is the fact that the majority of diagnostic mutations with low allele fraction (low AR) are not detected at relapse, thus questioning their clinical significance.5 Demonstration of the clinical significance of FLT3-ITD led to the evaluation of HSCT in this high-risk cohort. Initial studies demonstrated that HSCT abrogates the
3341
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.
2014 124: 3341-3342 doi:10.1182/blood-2014-10-605048
Allelic ratio: a marker of clonal dominance Soheil Meshinchi
Updated information and services can be found at: http://www.bloodjournal.org/content/124/23/3341.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.
REFERENCES 1. van Keimpema M, Gruneberg ¨ LJ, Mokry M, et al. FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-kB to promote survival of human B cells. Blood. 2014;124(23):3431-3440.
open-label, phase 2 study [abstract]. Blood. 2012;120(21). Abstract 686. 6. Yang Y, Shaffer AL III, Emre NC, et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell. 2012;21(6):723-737.
2. Abramson JS, Zelenetz AD. Recent advances in the treatment of non-Hodgkin’s lymphomas. J Natl Compr Canc Netw. 2013;11(5 suppl):671-675.
7. Katoh M, Igarashi M, Fukuda H, Nakagama H, Katoh M. Cancer genetics and genomics of human FOX family genes. Cancer Lett. 2013;328(2):198-206.
3. Zelenetz AD, Wierda WG, Abramson JS, et al; National Comprehensive Cancer Network. Non-Hodgkin’s lymphomas, version 1.2013. J Natl Compr Canc Netw. 2013;11(3):257-272, quiz 273.
8. Banham AH, Connors JM, Brown PJ, et al. Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma. Clin Cancer Res. 2005;11(3):1065-1072.
4. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503-511. 5. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (pci-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter,
9. Sagaert X, de Paepe P, Libbrecht L, et al. Forkhead box protein P1 expression in mucosa-associated lymphoid tissue lymphomas predicts poor prognosis and transformation to diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(16):2490-2497. © 2014 by The American Society of Hematology
l l l MYELOID NEOPLASIA
Comment on Schlenk et al, page 3441
Allelic ratio: a marker of clonal dominance ----------------------------------------------------------------------------------------------------Soheil Meshinchi
FRED HUTCHINSON CANCER RESEARCH INSTITUTE
In this issue of Blood, Schlenk et al provide compelling data on the prognostic implications of FMS-like tyrosine kinase 3 (FLT3)/internal tandem duplication allelic ratio (ITD-AR), as well as its impact on response to allogeneic stem cell transplantation.1
T
hey provide detailed analysis of data from a large cohort of patients with FLT3-ITD treated in 4 multicenter German-Austrian Acute Myeloid Leukemia (AML) Study Group (AMLSG) trials and correlate the variation in ITD-AR with response to induction chemotherapy and clinical outcome. Given the significant variation in ITD-AR and lack of a preestablished biological threshold, the authors establish a statistically defined cut-point for clinically meaningful ITD-AR of 0.51 for further correlation with clinical outcome. It is important to note that this ITD-AR is similar to those previously defined clinically defined thresholds.2 They demonstrate that those with high ITD-AR have a significantly worse complete remission (CR) rate and correspondingly poor survival and relapse. They further demonstrate that the adverse outcome of high ITD-AR is abrogated by stem cell transplantation. In contrast to patients with high ITD-AR, there appears to be no distinction between
those with low ITD-AR and those without FLT3-ITD (FLT3 wild type [FLT3/WT]) in terms of overall outcome or response to hematopoietic stem cell transplantation (HSCT). To discuss the role of varying ITD-AR in AML, one must address the underlying mechanism for such a wide variation in AR (ranging from 0.01 to .100), which is the ultimate representation of the enormous complexity and genomic heterogeneity of FLT3-ITD–positive AML, as multiple factors contribute to this variation in ITD-AR. The most obvious of these factors is that ITD-AR is a representation of the state of clonal dominance (or lack thereof) of the mutation, where in those with high ITD-AR, FLT3-ITD is the dominant lesion and is present in the majority or all of the leukemic cells. In contrast, in those with low ITD-AR, FLT3-ITD is present in a minor subclone within the bulk leukemic population. Single cell genotyping of leukemic cells from patients with varying ITD-AR established
BLOOD, 27 NOVEMBER 2014 x VOLUME 124, NUMBER 23
the genomic heterogeneity in FLT3-ITD AML, demonstrating that FLT3-ITD may be present in a major (high ITD-AR) or minor (low ITD-AR) subset of leukemic cells, and defined an association of ITD-AR with the proportion of individual cells that harbor FLT3-ITD and contribute to the final ITD-AR value.3 ITD-AR is further impacted by the associated copy-neutral loss of heterozygosity (LOH) of chromosome 13q (13q CN-LOH) in patients with FLT3-ITD. This genomic variant is the result of a homologous recombination-mediated process where the WT allele is replaced by the allele with FLT3-ITD, resulting in loss of heterozygosity (without copy number loss), leading to evolution of homozygous ITD. Single cell genotyping further demonstrated that in patients with FLT3-ITD, leukemic cells are composed of a mixture of homozygous FLT3-ITD, heterozygous FLT3-ITD, and FLT3/WT, with a final value of ITD-AR determined by the proportion of each genotypic subset.3 The fact that 13q CN-LOH is uniquely observed in the setting of FLT3-ITD may suggest a causal association between FLT3-ITD and evolution of this unique genomic event. Ultimately, ITD-AR represents the extent of the clonal dominance of FLT3-ITD (with contribution of 13q CN-LOH), where in those with high ITD-AR, FLT3-ITD is present in the majority of the leukemic cells and likely the dominant and driving genomic event. In contrast, in those with low ITD-AR, where FLT3-ITD is present in the minority of leukemic cells, FLT3-ITD is unlikely to be the driving event and contribute to leukemic relapse. The clinical impact of AR has been observed in other mutations by demonstration of the association of the AR of KIT and CBL mutations with outcome.4 These data suggest that we may need to alter our approach to evaluation of diagnostic mutations in AML and determine not only what the mutation is, but whether the mutation is a dominant, driving lesion or a minor variant. An additional layer of data that substantiates the significance of mutation burden at diagnosis is the fact that the majority of diagnostic mutations with low allele fraction (low AR) are not detected at relapse, thus questioning their clinical significance.5 Demonstration of the clinical significance of FLT3-ITD led to the evaluation of HSCT in this high-risk cohort. Initial studies demonstrated that HSCT abrogates the
3341
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.
2014 124: 3341-3342 doi:10.1182/blood-2014-10-605048
Allelic ratio: a marker of clonal dominance Soheil Meshinchi
Updated information and services can be found at: http://www.bloodjournal.org/content/124/23/3341.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.
