FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2012606483> ?p ?o ?g. }

• W2012606483 endingPage "422" @default.
• W2012606483 startingPage "421" @default.
• W2012606483 abstract "Recent studies (Shlush et al., 2014Shlush L.I. Zandi S. Mitchell A. Chen W.C. Brandwein J.M. Gupta V. Kennedy J.A. Schimmer A.D. Schuh A.C. Yee K.W. et al.HALT Pan-Leukemia Gene Panel ConsortiumNature. 2014; 506: 328-333Crossref PubMed Scopus (1032) Google Scholar, Corces-Zimmerman et al., 2014Corces-Zimmerman M.R. Hong W.-J. Weissman I.L. Medeiros B.C. Majeti R. Proc. Natl. Acad. Sci. USA. 2014; 111: 2548-2553Crossref PubMed Scopus (524) Google Scholar) have demonstrated that leukemias develop from hematopoietic stem cells that acquire preleukemic mutations, allowing clonal expansion and subsequent acquisition of mutations leading to cancer. Preleukemic cells survive chemotherapy and serve as reservoirs for disease, generating new clones and leading to relapse. Recent studies (Shlush et al., 2014Shlush L.I. Zandi S. Mitchell A. Chen W.C. Brandwein J.M. Gupta V. Kennedy J.A. Schimmer A.D. Schuh A.C. Yee K.W. et al.HALT Pan-Leukemia Gene Panel ConsortiumNature. 2014; 506: 328-333Crossref PubMed Scopus (1032) Google Scholar, Corces-Zimmerman et al., 2014Corces-Zimmerman M.R. Hong W.-J. Weissman I.L. Medeiros B.C. Majeti R. Proc. Natl. Acad. Sci. USA. 2014; 111: 2548-2553Crossref PubMed Scopus (524) Google Scholar) have demonstrated that leukemias develop from hematopoietic stem cells that acquire preleukemic mutations, allowing clonal expansion and subsequent acquisition of mutations leading to cancer. Preleukemic cells survive chemotherapy and serve as reservoirs for disease, generating new clones and leading to relapse. Acute myeloid leukemia (AML) is a malignancy in which hematopoietic stem and progenitor cells (HSPCs) give rise to clonal populations of primitive cancer cells with impaired differentiation, known as “blasts.” These clones vary in dominance over time, some with distinct, and others with overlapping, mutational profiles. The application of next-generation sequencing to define the serial acquisition of genetic mutations has allowed a preliminary view of the evolution of primary AML by The Cancer Genome Atlas (TCGA) consortium (Cancer Genome Atlas Research Network, 2013Cancer Genome Atlas Research NetworkN. Engl. J. Med. 2013; 368: 2059-2074Crossref PubMed Scopus (3289) Google Scholar) and of relapsed disease (Ding et al., 2012Ding L. Ley T.J. Larson D.E. Miller C.A. Koboldt D.C. Welch J.S. Ritchey J.K. Young M.A. Lamprecht T. McLellan M.D. et al.Nature. 2012; 481: 506-510Crossref PubMed Scopus (1539) Google Scholar). Mutational analysis of AML patient cohorts has also begun to define the prognostic value of these mutations (Patel et al., 2012Patel J.P. Gönen M. Figueroa M.E. Fernandez H. Sun Z. Racevskis J. Van Vlierberghe P. Dolgalev I. Thomas S. Aminova O. et al.N. Engl. J. Med. 2012; 366: 1079-1089Crossref PubMed Scopus (1450) Google Scholar). However, an in-depth understanding of the evolutionary origins of leukemic clones is still lacking. Two recent studies by the Dick (Shlush et al., 2014Shlush L.I. Zandi S. Mitchell A. Chen W.C. Brandwein J.M. Gupta V. Kennedy J.A. Schimmer A.D. Schuh A.C. Yee K.W. et al.HALT Pan-Leukemia Gene Panel ConsortiumNature. 2014; 506: 328-333Crossref PubMed Scopus (1032) Google Scholar) and Majeti (Corces-Zimmerman et al., 2014Corces-Zimmerman M.R. Hong W.-J. Weissman I.L. Medeiros B.C. Majeti R. Proc. Natl. Acad. Sci. USA. 2014; 111: 2548-2553Crossref PubMed Scopus (524) Google Scholar) groups now demonstrate that HSPCs acquire preleukemic mutations. These preleukemic stem cells contribute to normal blood development, harbor a selective growth advantage compared to their nonmutated normal stem/progenitor counterparts, and can subsequently gain additional mutations that confer full malignant potential (Figure 1). The fundamental shift in thinking provided by these collective studies is the demonstration that nonmalignant precursors give rise to a collection of preleukemic cells that persist after treatment and generate multiple waves of malignant clones over time. Some of these new clones are related to the original malignant clone, whereas others resemble the preleukemic HSPCs but contain a unique set of downstream mutations and are independent from the original dominant malignant clone. These preleukemic HSPCs are classified as nonmalignant based on their ability to generate cells in nonmalignant lineages (e.g., B and T cells). Shlush et al. performed deep sequencing on 103 candidate genes frequently mutated in AMLs (Shlush et al., 2014Shlush L.I. Zandi S. Mitchell A. Chen W.C. Brandwein J.M. Gupta V. Kennedy J.A. Schimmer A.D. Schuh A.C. Yee K.W. et al.HALT Pan-Leukemia Gene Panel ConsortiumNature. 2014; 506: 328-333Crossref PubMed Scopus (1032) Google Scholar). They used normal T lymphocytes as a surrogate for the occurrence of mutations in HSPCs and compared mutational profiles to those obtained from leukemic blasts in the same blood sample. Using this methodology, they demonstrated that somatic DNMT3A mutations occur in an ancestral cell that generates both T cells and the dominant leukemic clone. DNMT3A mutations were shown to occur in specific HSPC populations including, but not limited to, HSPCs from a relapsed patient, megakaryocyte-erythroid progenitors (MEPs) and CD33+ myeloid cells from a patient in remission, and MEPs from a patient at diagnosis. Several patient blast samples had mutations in NPM1 not found in their normal T cells. Strikingly, NPM1 mutations were only observed with DNMT3A mutations, further suggesting that DNMT3A mutations are early events in leukemogenesis. The authors then demonstrated that preleukemic HSPCs survive after chemotherapy. By comparing allelic frequencies of DNMT3Amut at times of diagnosis, remission, and relapse, they found increased prevalence of the mutated allele at remission and relapse, suggesting that these early, preleukemic cells harboring DNMT3Amut could be a reservoir for recurrent disease. Furthermore, using xenograft repopulation assays, Shlush et al. established that DNMT3Amut-bearing HSPCs engraft and generate long-term multilineage reconstitution, and they demonstrated that these cells possess a competitive repopulation advantage over nonmutated HSPCs, similar to previous observations showing that murine Dnmt3a-deficient HSPCs demonstrate a growth advantage over wild-type cells (Challen et al., 2012Challen G.A. Sun D. Jeong M. Luo M. Jelinek J. Berg J.S. Bock C. Vasanthakumar A. Gu H. Xi Y. et al.Nat. Genet. 2012; 44: 23-31Crossref Scopus (787) Google Scholar). Previous work from the Majeti group, analyzing a small cohort of AML patients, suggested that preleukemic mutations are present in HSPCs (Jan et al., 2012Jan M. Snyder T.M. Corces-Zimmerman M.R. Vyas P. Weissman I.L. Quake S.R. Majeti R. Sci. Transl. Med. 2012; 4: 149ra118Crossref PubMed Scopus (544) Google Scholar). Expanding on this earlier work, Corces-Zimmerman et al., 2014Corces-Zimmerman M.R. Hong W.-J. Weissman I.L. Medeiros B.C. Majeti R. Proc. Natl. Acad. Sci. USA. 2014; 111: 2548-2553Crossref PubMed Scopus (524) Google Scholar now identify preleukemic mutations in FACS-purified HSPCs from a larger cohort of patients manifesting a broader spectrum of AML. Similar to the Dick group, they found that “preleukemic” HSPCs can generate long-term myeloid and lymphoid engraftment in mice. The authors define mutations in IDH2, DNMT3A, ASXL1, and IKZF1 in the HSPC population and in leukemic cells, and in certain cases, in a fraction of sorted B and T cells at diagnosis. This indicates a clear contribution of the preleukemic HSPCs to overall hematopoiesis. The authors observe distinct patterns of mutation acquisition, with about half of the recurring mutations being classified as early, mostly in genes involved in DNA methylation, chromatin modification, and chromatin topology, and the other half of mutations classified as late, mostly within genes encoding proteins important in cell signaling and proliferation. Similar to the findings of the Dick group, the authors find that DNMT3A mutations were present in preleukemic HSPCs in 75% of patients, and additionally, that 80% of patients also harbored preleukemic IDH1/2 mutations. These mutations are found in the heterozygous state, implying that they can have dominant effects over the normal allele (Kim et al., 2013Kim S.J. Zhao H. Hardikar S. Singh A.K. Goodell M.A. Chen T. Blood. 2013; 122: 4086-4089Crossref PubMed Scopus (126) Google Scholar). Importantly, Corces-Zimmerman et al. found that preleukemic HSPCs are not eradicated by chemotherapy. Using bone marrow samples from patients in remission, as well as from patients with relapsed disease, the authors find that preleukemic HSPCs survive chemotherapy, persist during remission, and generate new waves of clones leading to relapse. They also found new mutations acquired during relapse that were not present at diagnosis or during remission, indicating that in some cases, a different HSPC clone may lead to the origin of relapsed disease. Majeti and colleagues make the important point that there are multiple pathways to relapsed AML (Corces-Zimmerman et al., 2014Corces-Zimmerman M.R. Hong W.-J. Weissman I.L. Medeiros B.C. Majeti R. Proc. Natl. Acad. Sci. USA. 2014; 111: 2548-2553Crossref PubMed Scopus (524) Google Scholar): cells that are refractory to initial therapy; clonal evolution from the original clone; growth of new subclones present at diagnosis; and new clones arising from a preleukemic HSPC. These studies raise additional questions. For instance, will similar evolutionary patterns be identified for AMLs driven by recurring translocations or mutations other than DNMT3A or IDH2? What other early mutations drive the development of preleukemic HSPCs? Given that normal HSPCs acquire mutations with age (Welch et al., 2012Welch J.S. Ley T.J. Link D.C. Miller C.A. Larson D.E. Koboldt D.C. Wartman L.D. Lamprecht T.L. Liu F. Xia J. et al.Cell. 2012; 150: 264-278Abstract Full Text Full Text PDF PubMed Scopus (1174) Google Scholar), how often do these mutations generate HSPCs? TET2, another gene in the epigenetic pathway, for example, can be mutated in elderly individuals with clonal hematopoiesis but without overt malignancy (Busque et al., 2012Busque L. Patel J.P. Figueroa M.E. Vasanthakumar A. Provost S. Hamilou Z. Mollica L. Li J. Viale A. Heguy A. et al.Nat. Genet. 2012; 44: 1179-1181Crossref PubMed Scopus (586) Google Scholar). Do mutations that generate a preleukemic HSPC population always involve a gene that encodes a chromatin-remodeling protein? How does AML arise from preleukemic HSCs that show no genetic mutations? What additional pathways lead to disease relapse? Reflecting on Darwin’s writing, “I have called this principle, by which each slight variation, if useful, is preserved, by the term of Natural Selection...,” it is remarkable to think that this statement is still relevant to our work today, more than 150 years after Darwin's words were published in 1859. One can almost imagine that Darwin wrote in response to the findings of these two outstanding papers." @default.
• W2012606483 created "2016-06-24" @default.
• W2012606483 creator A5013266798 @default.
• W2012606483 creator A5065240782 @default.
• W2012606483 date "2014-04-01" @default.
• W2012606483 modified "2023-09-27" @default.
• W2012606483 title "On the Origin of Leukemic Species" @default.
• W2012606483 cites W1255676896 @default.
• W2012606483 cites W1998367819 @default.
• W2012606483 cites W2012753533 @default.
• W2012606483 cites W2041191257 @default.
• W2012606483 cites W2055521874 @default.
• W2012606483 cites W2076031927 @default.
• W2012606483 cites W2080486691 @default.
• W2012606483 cites W2093144236 @default.
• W2012606483 cites W2115707319 @default.
• W2012606483 cites W2148965443 @default.
• W2012606483 doi "https://doi.org/10.1016/j.stem.2014.03.008" @default.
• W2012606483 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24702991" @default.
• W2012606483 hasPublicationYear "2014" @default.
• W2012606483 type Work @default.
• W2012606483 sameAs 2012606483 @default.
• W2012606483 citedByCount "6" @default.
• W2012606483 countsByYear W20126064832014 @default.
• W2012606483 countsByYear W20126064832015 @default.
• W2012606483 countsByYear W20126064832016 @default.
• W2012606483 countsByYear W20126064832017 @default.
• W2012606483 countsByYear W20126064832018 @default.
• W2012606483 crossrefType "journal-article" @default.
• W2012606483 hasAuthorship W2012606483A5013266798 @default.
• W2012606483 hasAuthorship W2012606483A5065240782 @default.
• W2012606483 hasBestOaLocation W20126064831 @default.
• W2012606483 hasConcept C70721500 @default.
• W2012606483 hasConcept C78458016 @default.
• W2012606483 hasConcept C86803240 @default.
• W2012606483 hasConceptScore W2012606483C70721500 @default.
• W2012606483 hasConceptScore W2012606483C78458016 @default.
• W2012606483 hasConceptScore W2012606483C86803240 @default.
• W2012606483 hasIssue "4" @default.
• W2012606483 hasLocation W20126064831 @default.
• W2012606483 hasLocation W20126064832 @default.
• W2012606483 hasOpenAccess W2012606483 @default.
• W2012606483 hasPrimaryLocation W20126064831 @default.
• W2012606483 hasRelatedWork W1828955125 @default.
• W2012606483 hasRelatedWork W1997770566 @default.
• W2012606483 hasRelatedWork W2006264290 @default.
• W2012606483 hasRelatedWork W2034736453 @default.
• W2012606483 hasRelatedWork W2061542922 @default.
• W2012606483 hasRelatedWork W2110450140 @default.
• W2012606483 hasRelatedWork W3048727301 @default.
• W2012606483 hasRelatedWork W4235748225 @default.
• W2012606483 hasRelatedWork W4236969087 @default.
• W2012606483 hasRelatedWork W4250812939 @default.
• W2012606483 hasVolume "14" @default.
• W2012606483 isParatext "false" @default.
• W2012606483 isRetracted "false" @default.
• W2012606483 magId "2012606483" @default.
• W2012606483 workType "article" @default.