From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
through externalization of NET-associated degradative enzymes. Strategies, such as blocking GPCR and b2-integrin signaling, that are aimed at limiting NET formation in such scenarios warrant further exploration. Second, these studies generate new mechanistic insights into the communication between activated platelets and PMNs and the complex regulatory network tasked with ensuring that NET formation occurs at the right time, in the right place, and with the appropriate magnitude. The platelet-derived CCL5/CXCL4 heterodimer and b2-integrin ligand signaling now represent new targets for study in the areas of dysregulated NET formation in inflammation, autoimmunity, and thrombosis. Furthermore, while disruption of these outside-in, platelet-toPMN signaling pathways may suggest future therapeutic strategies for syndromes of sterile inflammation, MKEY and Mac-1 blocking antibodies represent reagents of immediate benefit in determining how dysregulated NET formation contributes to pathogenesis of other inflammatory syndromes such as sepsis, pneumonia, autoimmune diseases, and disorders of thrombosis. In vivo model systems for all of these disease states exist where MKEY could be tested in preclinical models to determine whether NET inhibition “heals” or “harms.” As a corollary, while signaling to NET formation through interactions of activated platelets with neutrophils is not the only way that NET formation is triggered, it may be a particularly important mechanism in vascular injury syndromes.7 Finally, at face value, the suggestion that inhibition of NET formation in the setting of acute infection might decrease inflammatory tissue damage without increasing the microbial load and allowing infection to spread unchecked seems dubious. Indeed, initial in vivo experiments using DNase to dismantle NETs in models of polymicrobial sepsis resulted in hypersusceptibility to infection.8,9 Nevertheless, an emerging body of evidence suggests that strategies aimed at inhibiting NET formation in the setting of severe sepsis or systemic inflammatory response syndrome may improve outcomes and increase survival.4 The studies by Rossaint et al, which establish the peptide MKEY and anti-Mac-1 antibodies as molecules capable of arresting NET formation by interrupting outside-in signaling from platelets to PMNs, represent a first step toward the development of the
2440
“ideal” inhibitor of NET formation: a neutrophil-specific, NET-inhibitory agent that preserves PMN respiratory burst, phagocytosis, intracellular bacterial killing, and other antimicrobial functions. Conflict-of-interest disclosure: The author declares no competing financial interests. n
manoeuvres for host protection. Curr Opin Hematol. 2013; 20(1):3-9. 5. Harris ES, Weyrich AS, Zimmerman GA. Lessons from rare maladies: leukocyte adhesion deficiency syndromes. Curr Opin Hematol. 2013;20(1):16-25. 6. McInturff AM, Cody MJ, Elliott EA, et al. Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 a. Blood. 2012;120(15): 3118-3125.
REFERENCES
7. Rondina MT, Weyrich AS, Zimmerman GA. Platelets as cellular effectors of inflammation in vascular diseases. Circ Res. 2013;112(11):1506-1519.
1. Rossaint J, Herter JM, Van Aken H, et al. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap mediated sterile inflammation. Blood. 2014;123(16):2573-2584.
8. McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe. 2012;12(3):324-333.
2. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004; 303(5663):1532-1535. 3. Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: is immunity the second function of chromatin? J Cell Biol. 2012;198(5):773-783.
9. Meng W, Paunel-G¨orgul¨ ¨ u A, Floh´e S, et al. Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial sepsis in mice. Crit Care. 2012;16(4):R137.
4. Saffarzadeh M, Preissner KT. Fighting against the dark side of neutrophil extracellular traps in disease:
© 2014 by The American Society of Hematology
l l l LYMPHOID NEOPLASIA
Comment on de Smith et al, page 2497
Genomic clues to ethnic differences in ALL ----------------------------------------------------------------------------------------------------Sharon A. Savage1
1
NATIONAL CANCER INSTITUTE
In this issue of Blood, de Smith et al, in a new case-control association study of polymorphisms in key immunologic genes KIR and HLA, provide further evidence that genetic variation may contribute to differences in pediatric acute lymphoblastic leukemia (ALL) incidence between Hispanic and non-Hispanic ethnic groups.1
I
t has long been recognized that there is a higher incidence of ALL in children of Hispanic ancestry (24.9 per million personyears) than in non-Hispanic whites (16.6 per million).2 Children of Hispanic ancestry also have significantly worse 5-year survival from ALL compared with non-Hispanic whites (77% vs 87%).3 The reasons for these differences between ethnicities are likely multifactorial, possibly due to a combination of genetic and environmental factors.4 The timing of infections and/or a dysregulated immune system are postulated to be key factors in ALL etiology.5 In addition, because an individual’s response to infection can be highly variable and ALL is a cancer of lymphoid cells, it has been hypothesized that genetic variants in immune system genes may contribute to ALL etiology. This effect could also be influenced
by population-specific genetic variants that control the immune response. Although many studies have been conducted, the results are inconsistent.4,6 Natural killer (NK) cells express killer cell immunoglobulin-like receptors (KIRs), which interact primarily with HLA-C ligands. The KIR gene family located on 19q13.4 consists of 14 genes and 2 pseudogenes encoding receptors that are expressed on NK cells.7 The KIR locus on 10q13.4 has 2 primary haplotypes, A and B; KIR A contains 1 activating gene and KIR B is more polymorphic and contains the other 5 activating genes. The 6 activating KIR genes encode receptors that activate NK-cell activity upon binding of ligands such as HLA-C1, HLA-C2, HLA-Bw4, and HLA-Bw6. In this issue, de Smith and colleagues performed a case-control study of the
BLOOD, 17 APRIL 2014 x VOLUME 123, NUMBER 16
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
Approaches to understanding the genetics underlying ethnic disparities in ALL etiology and outcome.
association between pediatric ALL and the activating and inhibitory KIR genes, as well as the HLA-C group 1 (C1), group 2 (C2), and HLA-Bw4 polymorphic residues.1 The 212 ALL cases (including 114 Hispanic and 76 non-Hispanic white) in this study were children younger than 15 years of age enrolled in the California Childhood Leukemia Study. The controls (128 Hispanic and 86 nonHispanic) were derived from the California Department of Public Health’s Genetic Disease Screening Program. This study showed that there was a statistically significant association between the KIR A haplotype (as well as the number of activating or inhibitory KIR genes) and ALL in the Hispanic cases but not in the non-Hispanic cases when compared with ethnically matched controls. The converse was found in the HLA-Bw4/Bw6 genetic variants when the association was present in the non-Hispanic cases but not in the Hispanic cases. There was no association between ALL and HLA-C1 or HLA-C2 in either population. In 2011, Almalte et al evaluated the 6 stimulating activating KIR genes in a casecontrol study of 100 B-cell ALL cases and 245 controls of French Canadian ancestry.8 This study found a statistically significant inverse association between the presence of
BLOOD, 17 APRIL 2014 x VOLUME 123, NUMBER 16
activating KIR genes and childhood ALL. These findings were consistent in a population of 45 non-French ancestry, white Canadian individuals. This study did not evaluate KIR inhibitory genes or haplotypes. Notably, no association was found between KIR variants and childhood ALL in a casecontrol study from Germany (92% German ancestry) of 185 B-cell ALL cases. This study included both activating and inhibitory KIR genotypes9 and haplotype analyses. Consistent with the German study,9 the current study of individuals from California did not find an association between KIR polymorphisms and ALL in non-Hispanic whites.1 As authors of all 3 studies point out, the discrepancies in their results could be due, in part, to differential accuracy of the genotyping methodology across the KIR locus, and/or small differences between the genetic background of the populations studied.1,8,9 Although these 3 studies evaluated the KIR locus, they did not use the same genotyping methods or analyze the data in the same manner. Only the 6 activating genes were evaluated in the French Canadian study. Both activating and inhibitory KIR genes, as well as haplotype analyses, were studied in the German and California studies.
It is intriguing to consider that an important component of ALL etiology could be due to population-specific genetic variants. Variants in ARID5B and PIP4K2A loci are differentially associated with ALL risk based on ethnicity.4 The concept of evaluating the underlying population’s genetic structure was successfully applied through the use of mapping by admixture linkage disequibrium in a genome-wide association study (GWAS) of relapse after ALL therapy.10 That study found there were specific ancestry-related genetic differences associated with relapse, even after adjusting for known prognostic factors, that could partially explain the differences in survival between ethnic groups. In contrast, studies across key immune loci, such as the expanded major histocompatibility complex, have not consistently found differences between ethnicity, genetic variation, and ALL.6 The finding of de Smith et al that HLA-Bw4 was associated with ALL in non-Hispanic whites but not in Hispanic individuals, coupled with the opposite finding in the association between KIR haplotypes and ALL in Hispanics, may provide a clue as a potential connection between these loci and ALL risk in different ethnic groups. Differences in the immune response as well as environmental exposures could be key components of the disparities seen in both ALL incidence and clinical outcomes between Hispanic and non-Hispanic individuals with ALL. Epidemiology and genetic association studies have yielded important insights into these possible links, but many questions remain, due, in part, to the challenges in studying a relatively rare cancer. Many ALL etiology studies have limited statistical power due to their small sample sizes. GWAS have taught us that the effects of population stratification can be significant in case-control studies utilizing self-identified ethnicities. Future studies of connections between genetic variation in the immune system and ALL would benefit from careful evaluation of the underlying population structure and the creation of genetically matched controls. This approach, coupled with detailed environmental exposure assessments, has the potential to help sort out some of the reasons for inconsistent study results and to greatly advance our understanding of ALL etiology. Conflict-of-interest disclosure: The author declares no competing financial interests. n
2441
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
REFERENCES 1. de Smith AJ, Walsh KM, Ladner MB, et al. The role of KIR genes and their cognate HLA class I ligands in childhood acute lymphoblastic leukemia. Blood. 2014; 123(16):2497-2503. 2. Dores GM, Devesa SS, Curtis RE, Linet MS, Morton LM. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood. 2012;119(1):34-43. 3. Goggins WB, Lo FF. Racial and ethnic disparities in survival of US children with acute lymphoblastic leukemia: evidence from the SEER database 1988-2008. Cancer Causes Control. 2012;23(5):737-743. 4. Lim JY, Bhatia S, Robison LL, Yang JJ. Genomics of racial and ethnic disparities in childhood acute lymphoblastic leukemia [published online ahead of print December 30, 2013]. Cancer. 5. Greaves M. Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer. 2006;6(3):193-203.
6. Urayama KY, Thompson PD, Taylor M, Trachtenberg EA, Chokkalingam AP. Genetic variation in the extended major histocompatibility complex and susceptibility to childhood acute lymphoblastic leukemia: a review of the evidence. Front Oncol. 2013;3:300. 7. Middleton D, Gonzelez F. The extensive polymorphism of KIR genes. Immunology. 2010;129(1):8-19. 8. Almalte Z, Samarani S, Iannello A, et al. Novel associations between activating killer-cell immunoglobulinlike receptor genes and childhood leukemia. Blood. 2011; 118(5):1323-1328. 9. Babor F, Manser A, Sch¨onberg K, et al. Lack of association between KIR genes and acute lymphoblastic leukemia in children. Blood. 2012; 120(13):2770-2772. 10. Yang JJ, Cheng C, Devidas M, et al. Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat Genet. 2011;43(3):237-241.
l l l LYMPHOID NEOPLASIA
Comment on Sawyer et al, page 2504
Jumping translocations and high-risk myeloma ----------------------------------------------------------------------------------------------------Gareth J. Morgan1
1
INSTITUTE OF CANCER RESEARCH
In this issue of Blood, Sawyer et al show that jumping translocations of chromosome 1q constitute a mechanism by which widespread damage to the myeloma genome can occur, driving the progression of standard to high-risk clinical behavior.1 The description of this type of disease-specific mechanism pushing disease forward is an important step forward in understanding the biology of myeloma, because although we understand many of the genetic lesions present in myeloma, we have little insight into the mechanisms that cause them, especially those responsible for disease progression.
W
ith the application of global genetic technologies to characterize the myeloma genome, we are beginning to define the genetic lesions that transform a normal plasma cell into a cell with the features of a myeloma-propagating cell (MPC). This cell initiates the myeloma clone and subsequently evolves, leading to the monoclonal gammopathy of undetermined significance, smouldering multiple myeloma and multiple myeloma.2 Importantly, when we consider how these lesions interact to drive this process forward, a simplistic reductionist approach is to consider them as either initiating or progression events that sustain the evolution of the clone once it has been established. In myeloma, the known initiating lesions include chromosomal translocations into the Ig gene loci, mediated by a mechanism involving predominantly abnormal class-switch
2442
recombination but also involving receptor revision and possibly VDJ recombination.3 The other large subgroup of myeloma is initiated by the gain of whole chromosomes, the so-called hyperdiploid group, but little is known of the exact mechanism by which this arises. Subsequent to its initiation, the progression of myeloma is driven via the acquisition of genetic lesions, which collaborate with the initiating event to improve the survival and genetic diversity of the MPCs, which subsequently come to clonally dominate the myeloma survival niches according to Darwinian principles.4,5 The full spectrum of these genetic events, the order in which they occur, and collaborating combinations is not well defined.6 However, we know that the genetic lesions are either activated or inactivated by a number of molecular mechanisms, including interstitial
copy number gain, activating mutation, chromosomal translocation, or via loss of copy number or inactivating mutation. The full extent of copy-number gains, losses, and mutational spectrum of myeloma has been extensively reported recently.7 Of these lesions, the most important clinically are the t(4;14) 1q1 and 17p2, all of which are associated with adverse clinical outcomes. Interestingly, these lesions tend to occur together more than would be expected by chance, and in this situation they have a worse clinical outcome.8 Despite these recent successes in describing the genetics of myeloma, we have little if any idea of the causative mechanisms leading to their formation. Such mechanisms could either be random, with the cells carrying them coming to dominate because of the selective advantage they confer, or alternatively there could be specific and recurrent genetic mechanisms leading to the deregulation of a set of collaborating genes giving rise to aggressive clinical behavior. An answer to this important question would represent a significant step forward in our attempts to predict clinical outcome and could also open the way to specific clinical interventions. Interestingly, there are 2 loci where this question could be specifically addressed. The first example is MYC, a critical myeloma oncogene located at 8q24. We know that MYC is deregulated by mechanisms involving translocation both to the Ig locus and to superenhancers at other sites.9 The other locus where mechanistic insights may be gained is chromosome 1q, which is the most frequently gained chromosomal locus in myeloma (40%) and has an important negative impact on prognosis. Interestingly, until now the biological impact, the relevant deregulated gene, and the mechanism underlying the gain of copy number was unknown. The authors have published previously on the importance of jumping translocations at 1q12, designated as JT1q12, which is potentially the result of hypermethylation of the 1q12 pericentromeric heterochromatin. This region is special because it is the largest single block of late-replicating highly replicating satellite II/III DNA, which is known to contain unstable segmental duplications that could underlie the development of jumping translocations into this region.
BLOOD, 17 APRIL 2014 x VOLUME 123, NUMBER 16
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 123: 2440-2442 doi:10.1182/blood-2014-02-557330
Genomic clues to ethnic differences in ALL Sharon A. Savage
Updated information and services can be found at: http://www.bloodjournal.org/content/123/16/2440.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.
through externalization of NET-associated degradative enzymes. Strategies, such as blocking GPCR and b2-integrin signaling, that are aimed at limiting NET formation in such scenarios warrant further exploration. Second, these studies generate new mechanistic insights into the communication between activated platelets and PMNs and the complex regulatory network tasked with ensuring that NET formation occurs at the right time, in the right place, and with the appropriate magnitude. The platelet-derived CCL5/CXCL4 heterodimer and b2-integrin ligand signaling now represent new targets for study in the areas of dysregulated NET formation in inflammation, autoimmunity, and thrombosis. Furthermore, while disruption of these outside-in, platelet-toPMN signaling pathways may suggest future therapeutic strategies for syndromes of sterile inflammation, MKEY and Mac-1 blocking antibodies represent reagents of immediate benefit in determining how dysregulated NET formation contributes to pathogenesis of other inflammatory syndromes such as sepsis, pneumonia, autoimmune diseases, and disorders of thrombosis. In vivo model systems for all of these disease states exist where MKEY could be tested in preclinical models to determine whether NET inhibition “heals” or “harms.” As a corollary, while signaling to NET formation through interactions of activated platelets with neutrophils is not the only way that NET formation is triggered, it may be a particularly important mechanism in vascular injury syndromes.7 Finally, at face value, the suggestion that inhibition of NET formation in the setting of acute infection might decrease inflammatory tissue damage without increasing the microbial load and allowing infection to spread unchecked seems dubious. Indeed, initial in vivo experiments using DNase to dismantle NETs in models of polymicrobial sepsis resulted in hypersusceptibility to infection.8,9 Nevertheless, an emerging body of evidence suggests that strategies aimed at inhibiting NET formation in the setting of severe sepsis or systemic inflammatory response syndrome may improve outcomes and increase survival.4 The studies by Rossaint et al, which establish the peptide MKEY and anti-Mac-1 antibodies as molecules capable of arresting NET formation by interrupting outside-in signaling from platelets to PMNs, represent a first step toward the development of the
2440
“ideal” inhibitor of NET formation: a neutrophil-specific, NET-inhibitory agent that preserves PMN respiratory burst, phagocytosis, intracellular bacterial killing, and other antimicrobial functions. Conflict-of-interest disclosure: The author declares no competing financial interests. n
manoeuvres for host protection. Curr Opin Hematol. 2013; 20(1):3-9. 5. Harris ES, Weyrich AS, Zimmerman GA. Lessons from rare maladies: leukocyte adhesion deficiency syndromes. Curr Opin Hematol. 2013;20(1):16-25. 6. McInturff AM, Cody MJ, Elliott EA, et al. Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 a. Blood. 2012;120(15): 3118-3125.
REFERENCES
7. Rondina MT, Weyrich AS, Zimmerman GA. Platelets as cellular effectors of inflammation in vascular diseases. Circ Res. 2013;112(11):1506-1519.
1. Rossaint J, Herter JM, Van Aken H, et al. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap mediated sterile inflammation. Blood. 2014;123(16):2573-2584.
8. McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe. 2012;12(3):324-333.
2. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004; 303(5663):1532-1535. 3. Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: is immunity the second function of chromatin? J Cell Biol. 2012;198(5):773-783.
9. Meng W, Paunel-G¨orgul¨ ¨ u A, Floh´e S, et al. Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial sepsis in mice. Crit Care. 2012;16(4):R137.
4. Saffarzadeh M, Preissner KT. Fighting against the dark side of neutrophil extracellular traps in disease:
© 2014 by The American Society of Hematology
l l l LYMPHOID NEOPLASIA
Comment on de Smith et al, page 2497
Genomic clues to ethnic differences in ALL ----------------------------------------------------------------------------------------------------Sharon A. Savage1
1
NATIONAL CANCER INSTITUTE
In this issue of Blood, de Smith et al, in a new case-control association study of polymorphisms in key immunologic genes KIR and HLA, provide further evidence that genetic variation may contribute to differences in pediatric acute lymphoblastic leukemia (ALL) incidence between Hispanic and non-Hispanic ethnic groups.1
I
t has long been recognized that there is a higher incidence of ALL in children of Hispanic ancestry (24.9 per million personyears) than in non-Hispanic whites (16.6 per million).2 Children of Hispanic ancestry also have significantly worse 5-year survival from ALL compared with non-Hispanic whites (77% vs 87%).3 The reasons for these differences between ethnicities are likely multifactorial, possibly due to a combination of genetic and environmental factors.4 The timing of infections and/or a dysregulated immune system are postulated to be key factors in ALL etiology.5 In addition, because an individual’s response to infection can be highly variable and ALL is a cancer of lymphoid cells, it has been hypothesized that genetic variants in immune system genes may contribute to ALL etiology. This effect could also be influenced
by population-specific genetic variants that control the immune response. Although many studies have been conducted, the results are inconsistent.4,6 Natural killer (NK) cells express killer cell immunoglobulin-like receptors (KIRs), which interact primarily with HLA-C ligands. The KIR gene family located on 19q13.4 consists of 14 genes and 2 pseudogenes encoding receptors that are expressed on NK cells.7 The KIR locus on 10q13.4 has 2 primary haplotypes, A and B; KIR A contains 1 activating gene and KIR B is more polymorphic and contains the other 5 activating genes. The 6 activating KIR genes encode receptors that activate NK-cell activity upon binding of ligands such as HLA-C1, HLA-C2, HLA-Bw4, and HLA-Bw6. In this issue, de Smith and colleagues performed a case-control study of the
BLOOD, 17 APRIL 2014 x VOLUME 123, NUMBER 16
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
Approaches to understanding the genetics underlying ethnic disparities in ALL etiology and outcome.
association between pediatric ALL and the activating and inhibitory KIR genes, as well as the HLA-C group 1 (C1), group 2 (C2), and HLA-Bw4 polymorphic residues.1 The 212 ALL cases (including 114 Hispanic and 76 non-Hispanic white) in this study were children younger than 15 years of age enrolled in the California Childhood Leukemia Study. The controls (128 Hispanic and 86 nonHispanic) were derived from the California Department of Public Health’s Genetic Disease Screening Program. This study showed that there was a statistically significant association between the KIR A haplotype (as well as the number of activating or inhibitory KIR genes) and ALL in the Hispanic cases but not in the non-Hispanic cases when compared with ethnically matched controls. The converse was found in the HLA-Bw4/Bw6 genetic variants when the association was present in the non-Hispanic cases but not in the Hispanic cases. There was no association between ALL and HLA-C1 or HLA-C2 in either population. In 2011, Almalte et al evaluated the 6 stimulating activating KIR genes in a casecontrol study of 100 B-cell ALL cases and 245 controls of French Canadian ancestry.8 This study found a statistically significant inverse association between the presence of
BLOOD, 17 APRIL 2014 x VOLUME 123, NUMBER 16
activating KIR genes and childhood ALL. These findings were consistent in a population of 45 non-French ancestry, white Canadian individuals. This study did not evaluate KIR inhibitory genes or haplotypes. Notably, no association was found between KIR variants and childhood ALL in a casecontrol study from Germany (92% German ancestry) of 185 B-cell ALL cases. This study included both activating and inhibitory KIR genotypes9 and haplotype analyses. Consistent with the German study,9 the current study of individuals from California did not find an association between KIR polymorphisms and ALL in non-Hispanic whites.1 As authors of all 3 studies point out, the discrepancies in their results could be due, in part, to differential accuracy of the genotyping methodology across the KIR locus, and/or small differences between the genetic background of the populations studied.1,8,9 Although these 3 studies evaluated the KIR locus, they did not use the same genotyping methods or analyze the data in the same manner. Only the 6 activating genes were evaluated in the French Canadian study. Both activating and inhibitory KIR genes, as well as haplotype analyses, were studied in the German and California studies.
It is intriguing to consider that an important component of ALL etiology could be due to population-specific genetic variants. Variants in ARID5B and PIP4K2A loci are differentially associated with ALL risk based on ethnicity.4 The concept of evaluating the underlying population’s genetic structure was successfully applied through the use of mapping by admixture linkage disequibrium in a genome-wide association study (GWAS) of relapse after ALL therapy.10 That study found there were specific ancestry-related genetic differences associated with relapse, even after adjusting for known prognostic factors, that could partially explain the differences in survival between ethnic groups. In contrast, studies across key immune loci, such as the expanded major histocompatibility complex, have not consistently found differences between ethnicity, genetic variation, and ALL.6 The finding of de Smith et al that HLA-Bw4 was associated with ALL in non-Hispanic whites but not in Hispanic individuals, coupled with the opposite finding in the association between KIR haplotypes and ALL in Hispanics, may provide a clue as a potential connection between these loci and ALL risk in different ethnic groups. Differences in the immune response as well as environmental exposures could be key components of the disparities seen in both ALL incidence and clinical outcomes between Hispanic and non-Hispanic individuals with ALL. Epidemiology and genetic association studies have yielded important insights into these possible links, but many questions remain, due, in part, to the challenges in studying a relatively rare cancer. Many ALL etiology studies have limited statistical power due to their small sample sizes. GWAS have taught us that the effects of population stratification can be significant in case-control studies utilizing self-identified ethnicities. Future studies of connections between genetic variation in the immune system and ALL would benefit from careful evaluation of the underlying population structure and the creation of genetically matched controls. This approach, coupled with detailed environmental exposure assessments, has the potential to help sort out some of the reasons for inconsistent study results and to greatly advance our understanding of ALL etiology. Conflict-of-interest disclosure: The author declares no competing financial interests. n
2441
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
REFERENCES 1. de Smith AJ, Walsh KM, Ladner MB, et al. The role of KIR genes and their cognate HLA class I ligands in childhood acute lymphoblastic leukemia. Blood. 2014; 123(16):2497-2503. 2. Dores GM, Devesa SS, Curtis RE, Linet MS, Morton LM. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood. 2012;119(1):34-43. 3. Goggins WB, Lo FF. Racial and ethnic disparities in survival of US children with acute lymphoblastic leukemia: evidence from the SEER database 1988-2008. Cancer Causes Control. 2012;23(5):737-743. 4. Lim JY, Bhatia S, Robison LL, Yang JJ. Genomics of racial and ethnic disparities in childhood acute lymphoblastic leukemia [published online ahead of print December 30, 2013]. Cancer. 5. Greaves M. Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer. 2006;6(3):193-203.
6. Urayama KY, Thompson PD, Taylor M, Trachtenberg EA, Chokkalingam AP. Genetic variation in the extended major histocompatibility complex and susceptibility to childhood acute lymphoblastic leukemia: a review of the evidence. Front Oncol. 2013;3:300. 7. Middleton D, Gonzelez F. The extensive polymorphism of KIR genes. Immunology. 2010;129(1):8-19. 8. Almalte Z, Samarani S, Iannello A, et al. Novel associations between activating killer-cell immunoglobulinlike receptor genes and childhood leukemia. Blood. 2011; 118(5):1323-1328. 9. Babor F, Manser A, Sch¨onberg K, et al. Lack of association between KIR genes and acute lymphoblastic leukemia in children. Blood. 2012; 120(13):2770-2772. 10. Yang JJ, Cheng C, Devidas M, et al. Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat Genet. 2011;43(3):237-241.
l l l LYMPHOID NEOPLASIA
Comment on Sawyer et al, page 2504
Jumping translocations and high-risk myeloma ----------------------------------------------------------------------------------------------------Gareth J. Morgan1
1
INSTITUTE OF CANCER RESEARCH
In this issue of Blood, Sawyer et al show that jumping translocations of chromosome 1q constitute a mechanism by which widespread damage to the myeloma genome can occur, driving the progression of standard to high-risk clinical behavior.1 The description of this type of disease-specific mechanism pushing disease forward is an important step forward in understanding the biology of myeloma, because although we understand many of the genetic lesions present in myeloma, we have little insight into the mechanisms that cause them, especially those responsible for disease progression.
W
ith the application of global genetic technologies to characterize the myeloma genome, we are beginning to define the genetic lesions that transform a normal plasma cell into a cell with the features of a myeloma-propagating cell (MPC). This cell initiates the myeloma clone and subsequently evolves, leading to the monoclonal gammopathy of undetermined significance, smouldering multiple myeloma and multiple myeloma.2 Importantly, when we consider how these lesions interact to drive this process forward, a simplistic reductionist approach is to consider them as either initiating or progression events that sustain the evolution of the clone once it has been established. In myeloma, the known initiating lesions include chromosomal translocations into the Ig gene loci, mediated by a mechanism involving predominantly abnormal class-switch
2442
recombination but also involving receptor revision and possibly VDJ recombination.3 The other large subgroup of myeloma is initiated by the gain of whole chromosomes, the so-called hyperdiploid group, but little is known of the exact mechanism by which this arises. Subsequent to its initiation, the progression of myeloma is driven via the acquisition of genetic lesions, which collaborate with the initiating event to improve the survival and genetic diversity of the MPCs, which subsequently come to clonally dominate the myeloma survival niches according to Darwinian principles.4,5 The full spectrum of these genetic events, the order in which they occur, and collaborating combinations is not well defined.6 However, we know that the genetic lesions are either activated or inactivated by a number of molecular mechanisms, including interstitial
copy number gain, activating mutation, chromosomal translocation, or via loss of copy number or inactivating mutation. The full extent of copy-number gains, losses, and mutational spectrum of myeloma has been extensively reported recently.7 Of these lesions, the most important clinically are the t(4;14) 1q1 and 17p2, all of which are associated with adverse clinical outcomes. Interestingly, these lesions tend to occur together more than would be expected by chance, and in this situation they have a worse clinical outcome.8 Despite these recent successes in describing the genetics of myeloma, we have little if any idea of the causative mechanisms leading to their formation. Such mechanisms could either be random, with the cells carrying them coming to dominate because of the selective advantage they confer, or alternatively there could be specific and recurrent genetic mechanisms leading to the deregulation of a set of collaborating genes giving rise to aggressive clinical behavior. An answer to this important question would represent a significant step forward in our attempts to predict clinical outcome and could also open the way to specific clinical interventions. Interestingly, there are 2 loci where this question could be specifically addressed. The first example is MYC, a critical myeloma oncogene located at 8q24. We know that MYC is deregulated by mechanisms involving translocation both to the Ig locus and to superenhancers at other sites.9 The other locus where mechanistic insights may be gained is chromosome 1q, which is the most frequently gained chromosomal locus in myeloma (40%) and has an important negative impact on prognosis. Interestingly, until now the biological impact, the relevant deregulated gene, and the mechanism underlying the gain of copy number was unknown. The authors have published previously on the importance of jumping translocations at 1q12, designated as JT1q12, which is potentially the result of hypermethylation of the 1q12 pericentromeric heterochromatin. This region is special because it is the largest single block of late-replicating highly replicating satellite II/III DNA, which is known to contain unstable segmental duplications that could underlie the development of jumping translocations into this region.
BLOOD, 17 APRIL 2014 x VOLUME 123, NUMBER 16
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 123: 2440-2442 doi:10.1182/blood-2014-02-557330
Genomic clues to ethnic differences in ALL Sharon A. Savage
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