From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
M1-linked polyubiquitination and is the focus of intense research. Surprisingly, Dubois and colleagues found that expression of a catalytically inactive HOIP mutant is able to restore reduced NF-kB signaling in HOIP-deficient cells to normal levels, indicating that HOIP mediates TCR signaling independent of its catalytic activity. This is further supported by the observation that silencing of OTULIN, a negative regulator of linear polyubiquitination, did not change TCR-induced NF-kB signaling. It should be mentioned that some modest linear polyubiquitination is detected in TCR-stimulated cells, indicating a possible role for linear ubiquitination in other TCR signaling pathways than NF-kB signaling. Dubois et al show that LUBAC is also part of the preassembled CBM complex in ABC-DLBCL cell lines and that combined silencing of all 3 LUBAC components inhibits constitutive NF-kB activation in these cells. Consistent with these findings and the known anti-apoptotic function of NF-kB, they show that LUBAC silencing also reduces cell survival. Together, these data indicate that LUBAC guarantees cell proliferation and survival of ABC-DLBCL by maintaining constitutive NF-kB activity. The results of Dubois et al suggest a novel catalytic-independent role of LUBAC in lymphocytes and B-cell lymphoma. The underlying molecular mechanism is still unclear but the finding that HOIP is necessary for the association between CBM and IKK complexes is indicative for an adaptor function. The exact mechanism could, however, be more complex as many ill-defined components compose the CBM complex. The data of Dubois et al complement the recent demonstration that BCR-mediated NF-kB activation does not require LUBAC catalytic activity in splenocytes.7 In addition, another parallel study also reports that LUBAC associates with the CBM complex in ABC-DLBCL and is required for cell viability.8 However, the latter study shows that LUBAC mediates constitutive linear polyubiquitination of the IKK adaptor protein NEMO in ABC-DLBCL, and describes 2 rare HOIP germline mutations that promote LUBAC E3 ubiquitin ligase activity and activate NF-kB in ABC-DLBCL. At first look, these findings do not fit the catalyticindependent role of LUBAC that is proposed by Dubois et al in this issue. However, it should be mentioned that they only analyzed the
BLOOD, 3 APRIL 2014 x VOLUME 123, NUMBER 14
dependency on HOIP catalytic activity in T cells and not in ABC-DLBCL cell lines. Nevertheless, the finding that LUBAC is part of the CBM complex and mediates NF-kB signaling and cell survival is of high importance for our understanding of the regulation of physiological and pathological signaling in adaptive immunity. The CBM complex is an attractive therapeutic target for diseases associated with aberrant lymphocyte activation and B-cell lymphomas, and recent developments using MALT1 protease inhibitors are very promising.9 A better knowledge of the function and regulation of LUBAC in the CBM complex may provide additional ways for therapeutic targeting. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Dubois SM, Alexia C, Wu Y, et al. A catalytic-independent role for the LUBAC in NF-kB activation upon antigen receptor engagement and in lymphoma cells. Blood. 2014; 123(14):2199-2203.
2. Hayden MS, Ghosh SNF. NF-kB in immunobiology. Cell Res. 2011;21(2):223-244. 3. Sun SC, Chang JH, Jin J. Regulation of nuclear factorkB in autoimmunity. Trends Immunol. 2013;34(6):282-289. 4. Shaffer AL III, Young RM, Staudt LM. Pathogenesis of human B cell lymphomas. Annu Rev Immunol. 2012;30:565-610. 5. Thome M, Charton JE, Pelzer C, Hailfinger S. Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harb Perspect Biol. 2010;2(9): a003004. 6. Iwai K. Diverse roles of the ubiquitin system in NF-kB activation. Biochim Biophys Acta. 2014;1843(1):129-136. 7. Sasaki Y, Sano S, Nakahara M, et al. Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells. EMBO J. 2013;32(18):2463-2476. 8. Yang Y, Schmitz R, Mitala JJ Jr, et al. Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. Cancer Discov. [published online ahead of print February 3, 2014]. doi: 10.1158/2159-8290.CD-13-0915. 9. Yang C, David L, Qiao Q, Damko E, Wu H. The CBM signalosome: potential therapeutic target for aggressive lymphoma? Cytokine Growth Factor Rev. [Published online ahead of print December 24, 2013]. doi:10.1016/ j.cytogfr.2013.12.008. © 2014 by The American Society of Hematology
l l l MYELOID NEOPLASIA
Comment on Lundberg et al, page 2220
Many roads lead to MPN ----------------------------------------------------------------------------------------------------Heike L. Pahl1
1
UNIVERSITY MEDICAL CENTER FREIBURG
In this issue of Blood, Lundberg et al correlate the presence of known mutations in patients with myeloproliferative neoplasms (MPNs) with clinical outcome, thereby proposing a molecular risk stratification.1
T
he clinical presentation of patients with MPNs is heterogeneous, and the individual disease course is difficult to predict at diagnosis. Although in some patients the disorder remains indolent for many years, others experience multiple complications and rapid disease progression. It is therefore gratifying to read that Lundberg et al can corroborate this clinical heterogeneity at the molecular level.1 The authors investigated the “clonal architecture” of MPNs, that is the nature of different mutations detected in individual patients and the order in which they appear. Because the authors selected known cancer genes for analysis, many of which have been previously shown to be affected in MPNs, the message of this study is less in the nature of the mutations found but rather in the variable
pattern of their acquisition, which this study demonstrates. However, it is noteworthy that in this cohort, mutations in some novel genes, such as p53 and NF-E2, appear to be more frequent than others, such as c-Cbl or c-Mpl, which have been known for several years.2-4 A model presented in Figure 5 of the Lundberg et al paper depicts the many different constellations observed and uses them to stratify patients by risk of leukemic transformation. As is the case in other myeloid neoplasias, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS),5,6 a higher number of mutations is associated with poorer outcome. In MDS, the number of mutations is likewise correlated with the time to leukemic transformation.6 The question remains, however, whether the acquisition of additional
2133
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
mutations is inherent in the disease process. If so, it would occur stochastically such that individual risk could not be assessed a priori. Alternatively, patients could present with high risk mutations at diagnosis—these then simply need to be identified and considered when assessing therapeutic options. One hypothesis for explaining the acquisition of mutations and the observed variability in disease progression is the presence of a “hypermutable state” in MPNs.7,8 In this model, individual patients are thought to acquire different additional mutations during disease progression, and the nature of these mutations directs the clinical phenotype. The data presented by Skoda’s group clearly argue against a hypermutable state in MPNs. The vast majority (95%) of all mutations detected were already present in the first sample analyzed. In addition, using 2 different methods, the authors calculate a mutation rate of 1 mutation in the genes analyzed in 45 to 66 patient-years. This calculation, however, raises 1 question. Of the 197 patients analyzed, 33% already carried $2 mutations. The average age at diagnosis in this patient cohort was 51 years for essential thrombocythemia (ET) and 58 or 61 years, respectively, for polycythemia vera (PV) and primary myelofibrosis (PMF) patients. Nonetheless, 27% of the ET patients had already acquired $2 mutations, in a time frame calculated to suffice only for 1 mutation. Prior to disease manifestation, therefore, some patients must have incurred a higher mutation rate. Because transformation to acute leukemia, which is often highly refractory to treatment, is clinically the most challenging complication experienced by these patients, early predictors of leukemic risk are of utmost importance. Lundberg et al show that mutations in the tumor suppressor p53 are present at very low levels (so-called “subclonal levels,” where a very small percentage of the patient’s cells carry the aberration) in a small number of MPN patients. With 1 exception, 4 of the 5 patients carrying p53 mutations transformed to AML, with a latency of between 5 and 10 years. Because the p53 mutations were observed at such low levels, modern sequencing technologies (next-generation sequencing [NGS]) are required for their detection. Given their clinical importance, detection of p53 mutations by NGS should be considered in MPN patients, especially in light of 1 unexpected observation in this data set: of
2134
the 5 patients in which p53 mutations were identified, 3 were diagnosed with ET, generally considered to carry a significantly lower risk of leukemic transformation than PV or especially PMF. Moreover, ET is frequently diagnosed at a younger age, as also seen in the current cohort. ET patients with p53 mutations therefore present with an unanticipated high risk, one that is inapparent by clinical means, but may frequently be good candidates for bone marrow transplantation (BMT). BMT is the only curative approach to MPNs and one that may preempt leukemic transformation. A similar argument may apply to select patients with TET2 mutations, which are also shown to be associated with poor outcome in this study. However, the rate of leukemic transformation in TET2-mutated patients was only 30% compared with the 80% in p53-mutated patients (with the caveat of small number errors in both cohorts); hence, the decision for BMT must consider this. The rapidly decreasing costs of NGS analysis may soon allow an economical use of this technology for the detection of clinical risk in MPN patients, a cohort that today appears undiscernibly heterogeneous in outcome. In this way, MPNs may follow the successful path forged by .10 years of molecularly guided therapeutic trials in AML, which have led to both improved molecular risk stratification and the development of targeted therapies for select molecularly defined groups of patients.9 Conflict-of-interest disclosure: The author declares no competing financial interests. n
REFERENCES 1. Lundberg P, Karow A, Nienhold R, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood. 2014;123(14): 2220-2228. 2. Jutzi JS, Bogeska R, Nikoloski G, et al. MPN patients harbor recurrent truncating mutations in transcription factor NF-E2. J Exp Med. 2013;210(5): 1003-1019. 3. Grand FH, Hidalgo-Curtis CE, Ernst T, et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood. 2009;113(24):6182-6192. 4. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3(7):e270. 5. Marcucci G, Haferlach T, D¨ohner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol. 2011;29(5): 475-486. 6. Papaemmanuil E, Gerstung M, Malcovati L, et al; Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22): 3616-3627, quiz 3699. 7. Jones AV, Chase A, Silver RT, et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet. 2009;41(4): 446-449. 8. Plo I, Nakatake M, Malivert L, et al. JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders. Blood. 2008;112(4): 1402-1412. 9. Dohner H, Gaidzik VI. Impact of genetic features on treatment decisions in AML. Hematology Am Soc Hematol Educ Program. 2011;2011:36-42.
© 2014 by The American Society of Hematology
l l l RED CELLS, IRON, & ERYTHROPOIESIS
Comment on Garcia-Santos et al, page 2269
Toward unraveling heme regulation ----------------------------------------------------------------------------------------------------Valentine Brousse1 and Wassim El Nemer2 1134
ˆ HOPITAL UNIVERSITAIRE NECKER-ENFANTS MALADES; 2INSERM UMRS
1
In this issue of Blood, Garcia-Santos et al advance the field of heme regulation, a highly complex process involving iron and globin metabolism. They focus on a key enzyme involved in heme catabolism, heme oxygenase 1 (HO-1), which, ironically, has been poorly investigated in erythroid cells, the largest pool of heme-containing cells.1 hey address for the first time the role of the inducible HO-1 during murine erythroid differentiation. Hemoproteins are involved in a broad spectrum of crucial biological functions,
T
including oxygen binding, oxygen metabolism, and electron transfer.2 Hemoglobin is the most abundant hemoprotein, and the highest amount is found in circulating red blood cells. A fine balance between heme synthesis and catabolism
BLOOD, 3 APRIL 2014 x VOLUME 123, NUMBER 14
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 123: 2133-2134 doi:10.1182/blood-2014-02-554709
Many roads lead to MPN Heike L. Pahl
Updated information and services can be found at: http://www.bloodjournal.org/content/123/14/2133.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.
M1-linked polyubiquitination and is the focus of intense research. Surprisingly, Dubois and colleagues found that expression of a catalytically inactive HOIP mutant is able to restore reduced NF-kB signaling in HOIP-deficient cells to normal levels, indicating that HOIP mediates TCR signaling independent of its catalytic activity. This is further supported by the observation that silencing of OTULIN, a negative regulator of linear polyubiquitination, did not change TCR-induced NF-kB signaling. It should be mentioned that some modest linear polyubiquitination is detected in TCR-stimulated cells, indicating a possible role for linear ubiquitination in other TCR signaling pathways than NF-kB signaling. Dubois et al show that LUBAC is also part of the preassembled CBM complex in ABC-DLBCL cell lines and that combined silencing of all 3 LUBAC components inhibits constitutive NF-kB activation in these cells. Consistent with these findings and the known anti-apoptotic function of NF-kB, they show that LUBAC silencing also reduces cell survival. Together, these data indicate that LUBAC guarantees cell proliferation and survival of ABC-DLBCL by maintaining constitutive NF-kB activity. The results of Dubois et al suggest a novel catalytic-independent role of LUBAC in lymphocytes and B-cell lymphoma. The underlying molecular mechanism is still unclear but the finding that HOIP is necessary for the association between CBM and IKK complexes is indicative for an adaptor function. The exact mechanism could, however, be more complex as many ill-defined components compose the CBM complex. The data of Dubois et al complement the recent demonstration that BCR-mediated NF-kB activation does not require LUBAC catalytic activity in splenocytes.7 In addition, another parallel study also reports that LUBAC associates with the CBM complex in ABC-DLBCL and is required for cell viability.8 However, the latter study shows that LUBAC mediates constitutive linear polyubiquitination of the IKK adaptor protein NEMO in ABC-DLBCL, and describes 2 rare HOIP germline mutations that promote LUBAC E3 ubiquitin ligase activity and activate NF-kB in ABC-DLBCL. At first look, these findings do not fit the catalyticindependent role of LUBAC that is proposed by Dubois et al in this issue. However, it should be mentioned that they only analyzed the
BLOOD, 3 APRIL 2014 x VOLUME 123, NUMBER 14
dependency on HOIP catalytic activity in T cells and not in ABC-DLBCL cell lines. Nevertheless, the finding that LUBAC is part of the CBM complex and mediates NF-kB signaling and cell survival is of high importance for our understanding of the regulation of physiological and pathological signaling in adaptive immunity. The CBM complex is an attractive therapeutic target for diseases associated with aberrant lymphocyte activation and B-cell lymphomas, and recent developments using MALT1 protease inhibitors are very promising.9 A better knowledge of the function and regulation of LUBAC in the CBM complex may provide additional ways for therapeutic targeting. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Dubois SM, Alexia C, Wu Y, et al. A catalytic-independent role for the LUBAC in NF-kB activation upon antigen receptor engagement and in lymphoma cells. Blood. 2014; 123(14):2199-2203.
2. Hayden MS, Ghosh SNF. NF-kB in immunobiology. Cell Res. 2011;21(2):223-244. 3. Sun SC, Chang JH, Jin J. Regulation of nuclear factorkB in autoimmunity. Trends Immunol. 2013;34(6):282-289. 4. Shaffer AL III, Young RM, Staudt LM. Pathogenesis of human B cell lymphomas. Annu Rev Immunol. 2012;30:565-610. 5. Thome M, Charton JE, Pelzer C, Hailfinger S. Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harb Perspect Biol. 2010;2(9): a003004. 6. Iwai K. Diverse roles of the ubiquitin system in NF-kB activation. Biochim Biophys Acta. 2014;1843(1):129-136. 7. Sasaki Y, Sano S, Nakahara M, et al. Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells. EMBO J. 2013;32(18):2463-2476. 8. Yang Y, Schmitz R, Mitala JJ Jr, et al. Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. Cancer Discov. [published online ahead of print February 3, 2014]. doi: 10.1158/2159-8290.CD-13-0915. 9. Yang C, David L, Qiao Q, Damko E, Wu H. The CBM signalosome: potential therapeutic target for aggressive lymphoma? Cytokine Growth Factor Rev. [Published online ahead of print December 24, 2013]. doi:10.1016/ j.cytogfr.2013.12.008. © 2014 by The American Society of Hematology
l l l MYELOID NEOPLASIA
Comment on Lundberg et al, page 2220
Many roads lead to MPN ----------------------------------------------------------------------------------------------------Heike L. Pahl1
1
UNIVERSITY MEDICAL CENTER FREIBURG
In this issue of Blood, Lundberg et al correlate the presence of known mutations in patients with myeloproliferative neoplasms (MPNs) with clinical outcome, thereby proposing a molecular risk stratification.1
T
he clinical presentation of patients with MPNs is heterogeneous, and the individual disease course is difficult to predict at diagnosis. Although in some patients the disorder remains indolent for many years, others experience multiple complications and rapid disease progression. It is therefore gratifying to read that Lundberg et al can corroborate this clinical heterogeneity at the molecular level.1 The authors investigated the “clonal architecture” of MPNs, that is the nature of different mutations detected in individual patients and the order in which they appear. Because the authors selected known cancer genes for analysis, many of which have been previously shown to be affected in MPNs, the message of this study is less in the nature of the mutations found but rather in the variable
pattern of their acquisition, which this study demonstrates. However, it is noteworthy that in this cohort, mutations in some novel genes, such as p53 and NF-E2, appear to be more frequent than others, such as c-Cbl or c-Mpl, which have been known for several years.2-4 A model presented in Figure 5 of the Lundberg et al paper depicts the many different constellations observed and uses them to stratify patients by risk of leukemic transformation. As is the case in other myeloid neoplasias, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS),5,6 a higher number of mutations is associated with poorer outcome. In MDS, the number of mutations is likewise correlated with the time to leukemic transformation.6 The question remains, however, whether the acquisition of additional
2133
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
mutations is inherent in the disease process. If so, it would occur stochastically such that individual risk could not be assessed a priori. Alternatively, patients could present with high risk mutations at diagnosis—these then simply need to be identified and considered when assessing therapeutic options. One hypothesis for explaining the acquisition of mutations and the observed variability in disease progression is the presence of a “hypermutable state” in MPNs.7,8 In this model, individual patients are thought to acquire different additional mutations during disease progression, and the nature of these mutations directs the clinical phenotype. The data presented by Skoda’s group clearly argue against a hypermutable state in MPNs. The vast majority (95%) of all mutations detected were already present in the first sample analyzed. In addition, using 2 different methods, the authors calculate a mutation rate of 1 mutation in the genes analyzed in 45 to 66 patient-years. This calculation, however, raises 1 question. Of the 197 patients analyzed, 33% already carried $2 mutations. The average age at diagnosis in this patient cohort was 51 years for essential thrombocythemia (ET) and 58 or 61 years, respectively, for polycythemia vera (PV) and primary myelofibrosis (PMF) patients. Nonetheless, 27% of the ET patients had already acquired $2 mutations, in a time frame calculated to suffice only for 1 mutation. Prior to disease manifestation, therefore, some patients must have incurred a higher mutation rate. Because transformation to acute leukemia, which is often highly refractory to treatment, is clinically the most challenging complication experienced by these patients, early predictors of leukemic risk are of utmost importance. Lundberg et al show that mutations in the tumor suppressor p53 are present at very low levels (so-called “subclonal levels,” where a very small percentage of the patient’s cells carry the aberration) in a small number of MPN patients. With 1 exception, 4 of the 5 patients carrying p53 mutations transformed to AML, with a latency of between 5 and 10 years. Because the p53 mutations were observed at such low levels, modern sequencing technologies (next-generation sequencing [NGS]) are required for their detection. Given their clinical importance, detection of p53 mutations by NGS should be considered in MPN patients, especially in light of 1 unexpected observation in this data set: of
2134
the 5 patients in which p53 mutations were identified, 3 were diagnosed with ET, generally considered to carry a significantly lower risk of leukemic transformation than PV or especially PMF. Moreover, ET is frequently diagnosed at a younger age, as also seen in the current cohort. ET patients with p53 mutations therefore present with an unanticipated high risk, one that is inapparent by clinical means, but may frequently be good candidates for bone marrow transplantation (BMT). BMT is the only curative approach to MPNs and one that may preempt leukemic transformation. A similar argument may apply to select patients with TET2 mutations, which are also shown to be associated with poor outcome in this study. However, the rate of leukemic transformation in TET2-mutated patients was only 30% compared with the 80% in p53-mutated patients (with the caveat of small number errors in both cohorts); hence, the decision for BMT must consider this. The rapidly decreasing costs of NGS analysis may soon allow an economical use of this technology for the detection of clinical risk in MPN patients, a cohort that today appears undiscernibly heterogeneous in outcome. In this way, MPNs may follow the successful path forged by .10 years of molecularly guided therapeutic trials in AML, which have led to both improved molecular risk stratification and the development of targeted therapies for select molecularly defined groups of patients.9 Conflict-of-interest disclosure: The author declares no competing financial interests. n
REFERENCES 1. Lundberg P, Karow A, Nienhold R, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood. 2014;123(14): 2220-2228. 2. Jutzi JS, Bogeska R, Nikoloski G, et al. MPN patients harbor recurrent truncating mutations in transcription factor NF-E2. J Exp Med. 2013;210(5): 1003-1019. 3. Grand FH, Hidalgo-Curtis CE, Ernst T, et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood. 2009;113(24):6182-6192. 4. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3(7):e270. 5. Marcucci G, Haferlach T, D¨ohner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol. 2011;29(5): 475-486. 6. Papaemmanuil E, Gerstung M, Malcovati L, et al; Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22): 3616-3627, quiz 3699. 7. Jones AV, Chase A, Silver RT, et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet. 2009;41(4): 446-449. 8. Plo I, Nakatake M, Malivert L, et al. JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders. Blood. 2008;112(4): 1402-1412. 9. Dohner H, Gaidzik VI. Impact of genetic features on treatment decisions in AML. Hematology Am Soc Hematol Educ Program. 2011;2011:36-42.
© 2014 by The American Society of Hematology
l l l RED CELLS, IRON, & ERYTHROPOIESIS
Comment on Garcia-Santos et al, page 2269
Toward unraveling heme regulation ----------------------------------------------------------------------------------------------------Valentine Brousse1 and Wassim El Nemer2 1134
ˆ HOPITAL UNIVERSITAIRE NECKER-ENFANTS MALADES; 2INSERM UMRS
1
In this issue of Blood, Garcia-Santos et al advance the field of heme regulation, a highly complex process involving iron and globin metabolism. They focus on a key enzyme involved in heme catabolism, heme oxygenase 1 (HO-1), which, ironically, has been poorly investigated in erythroid cells, the largest pool of heme-containing cells.1 hey address for the first time the role of the inducible HO-1 during murine erythroid differentiation. Hemoproteins are involved in a broad spectrum of crucial biological functions,
T
including oxygen binding, oxygen metabolism, and electron transfer.2 Hemoglobin is the most abundant hemoprotein, and the highest amount is found in circulating red blood cells. A fine balance between heme synthesis and catabolism
BLOOD, 3 APRIL 2014 x VOLUME 123, NUMBER 14
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 123: 2133-2134 doi:10.1182/blood-2014-02-554709
Many roads lead to MPN Heike L. Pahl
Updated information and services can be found at: http://www.bloodjournal.org/content/123/14/2133.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.
