Identification of pre-leukemic hematopoietic stem cells in acute leukemia
In acute myeloid leukemia (AML), the cell of origin, nature and biological consequences of initiating lesions and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukemic phase. Here, highly purified hematopoietic stem cells (HSC), p...
Gespeichert in:
| Veröffentlicht in: | Nature (London) 2014-02, Vol.506 (7488), p.328-333 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 333 |
|---|---|
| container_issue | 7488 |
| container_start_page | 328 |
| container_title | Nature (London) |
| container_volume | 506 |
| creator | Shlush, Liran I. Zandi, Sasan Mitchell, Amanda Chen, Weihsu Claire Brandwein, Joseph M. Gupta, Vikas Kennedy, James A. Schimmer, Aaron D. Schuh, Andre C. Yee, Karen W. McLeod, Jessica L. Doedens, Monica Medeiros, Jessie J.F. Marke, Rene Kim, Hyeoung Joon Lee, Kwon McPherson, John D. Hudson, Thomas J. Brown, Andrew M.K. Trinh, Quang M. Stein, Lincoln D. Minden, Mark D. Wang, Jean C.Y. Dick, John E. |
| description | In acute myeloid leukemia (AML), the cell of origin, nature and biological consequences of initiating lesions and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukemic phase. Here, highly purified hematopoietic stem cells (HSC), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent
DNMT3a
mutations (
DNMT3a
mut
) at high allele frequency, but without coincident
NPM1
mutations (
NPM1c
) present in AML blasts.
DNMT3a
mut
-bearing HSC exhibited multilineage repopulation advantage over non-mutated HSC in xenografts, establishing their identity as pre-leukemic-HSC (preL-HSC). preL-HSC were found in remission samples indicating that they survive chemotherapy. Thus
DNMT3a
mut
arises early in AML evolution, likely in HSC, leading to a clonally expanded pool of preL-HSC from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance. |
| doi_str_mv | 10.1038/nature13038 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmedcentral</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4991939</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>pubmedcentral_primary_oai_pubmedcentral_nih_gov_4991939</sourcerecordid><originalsourceid>FETCH-pubmedcentral_primary_oai_pubmedcentral_nih_gov_49919393</originalsourceid><addsrcrecordid>eNqljT1PwzAYhC0EalPoxB_wHwj4K4mzsCAQ3dmtt-4bavBHZDtI_HsydGFmujs9pztC7jl74Ezqxwh1ycjl6q9Iw9XQt6rXwzVpGBO6ZVr2W7Ir5ZMx1vFBbchWqE6ITuiGHA4njNVNzkJ1KdI00Tlj63H5wuAsPWOAmubksK6pVAzUoveFukjBLhXppQp35GYCX3B_0Vvy9Pry_vzWzssx4MmuNxm8mbMLkH9MAmf-kujO5iN9GzWOfJSj_PfAL7jZXEg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Identification of pre-leukemic hematopoietic stem cells in acute leukemia</title><source>Nature</source><source>Alma/SFX Local Collection</source><creator>Shlush, Liran I. ; Zandi, Sasan ; Mitchell, Amanda ; Chen, Weihsu Claire ; Brandwein, Joseph M. ; Gupta, Vikas ; Kennedy, James A. ; Schimmer, Aaron D. ; Schuh, Andre C. ; Yee, Karen W. ; McLeod, Jessica L. ; Doedens, Monica ; Medeiros, Jessie J.F. ; Marke, Rene ; Kim, Hyeoung Joon ; Lee, Kwon ; McPherson, John D. ; Hudson, Thomas J. ; Brown, Andrew M.K. ; Trinh, Quang M. ; Stein, Lincoln D. ; Minden, Mark D. ; Wang, Jean C.Y. ; Dick, John E.</creator><creatorcontrib>Shlush, Liran I. ; Zandi, Sasan ; Mitchell, Amanda ; Chen, Weihsu Claire ; Brandwein, Joseph M. ; Gupta, Vikas ; Kennedy, James A. ; Schimmer, Aaron D. ; Schuh, Andre C. ; Yee, Karen W. ; McLeod, Jessica L. ; Doedens, Monica ; Medeiros, Jessie J.F. ; Marke, Rene ; Kim, Hyeoung Joon ; Lee, Kwon ; McPherson, John D. ; Hudson, Thomas J. ; Brown, Andrew M.K. ; Trinh, Quang M. ; Stein, Lincoln D. ; Minden, Mark D. ; Wang, Jean C.Y. ; Dick, John E.</creatorcontrib><description>In acute myeloid leukemia (AML), the cell of origin, nature and biological consequences of initiating lesions and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukemic phase. Here, highly purified hematopoietic stem cells (HSC), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent
DNMT3a
mutations (
DNMT3a
mut
) at high allele frequency, but without coincident
NPM1
mutations (
NPM1c
) present in AML blasts.
DNMT3a
mut
-bearing HSC exhibited multilineage repopulation advantage over non-mutated HSC in xenografts, establishing their identity as pre-leukemic-HSC (preL-HSC). preL-HSC were found in remission samples indicating that they survive chemotherapy. Thus
DNMT3a
mut
arises early in AML evolution, likely in HSC, leading to a clonally expanded pool of preL-HSC from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature13038</identifier><identifier>PMID: 24522528</identifier><language>eng</language><ispartof>Nature (London), 2014-02, Vol.506 (7488), p.328-333</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids></links><search><creatorcontrib>Shlush, Liran I.</creatorcontrib><creatorcontrib>Zandi, Sasan</creatorcontrib><creatorcontrib>Mitchell, Amanda</creatorcontrib><creatorcontrib>Chen, Weihsu Claire</creatorcontrib><creatorcontrib>Brandwein, Joseph M.</creatorcontrib><creatorcontrib>Gupta, Vikas</creatorcontrib><creatorcontrib>Kennedy, James A.</creatorcontrib><creatorcontrib>Schimmer, Aaron D.</creatorcontrib><creatorcontrib>Schuh, Andre C.</creatorcontrib><creatorcontrib>Yee, Karen W.</creatorcontrib><creatorcontrib>McLeod, Jessica L.</creatorcontrib><creatorcontrib>Doedens, Monica</creatorcontrib><creatorcontrib>Medeiros, Jessie J.F.</creatorcontrib><creatorcontrib>Marke, Rene</creatorcontrib><creatorcontrib>Kim, Hyeoung Joon</creatorcontrib><creatorcontrib>Lee, Kwon</creatorcontrib><creatorcontrib>McPherson, John D.</creatorcontrib><creatorcontrib>Hudson, Thomas J.</creatorcontrib><creatorcontrib>Brown, Andrew M.K.</creatorcontrib><creatorcontrib>Trinh, Quang M.</creatorcontrib><creatorcontrib>Stein, Lincoln D.</creatorcontrib><creatorcontrib>Minden, Mark D.</creatorcontrib><creatorcontrib>Wang, Jean C.Y.</creatorcontrib><creatorcontrib>Dick, John E.</creatorcontrib><title>Identification of pre-leukemic hematopoietic stem cells in acute leukemia</title><title>Nature (London)</title><description>In acute myeloid leukemia (AML), the cell of origin, nature and biological consequences of initiating lesions and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukemic phase. Here, highly purified hematopoietic stem cells (HSC), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent
DNMT3a
mutations (
DNMT3a
mut
) at high allele frequency, but without coincident
NPM1
mutations (
NPM1c
) present in AML blasts.
DNMT3a
mut
-bearing HSC exhibited multilineage repopulation advantage over non-mutated HSC in xenografts, establishing their identity as pre-leukemic-HSC (preL-HSC). preL-HSC were found in remission samples indicating that they survive chemotherapy. Thus
DNMT3a
mut
arises early in AML evolution, likely in HSC, leading to a clonally expanded pool of preL-HSC from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.</description><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNqljT1PwzAYhC0EalPoxB_wHwj4K4mzsCAQ3dmtt-4bavBHZDtI_HsydGFmujs9pztC7jl74Ezqxwh1ycjl6q9Iw9XQt6rXwzVpGBO6ZVr2W7Ir5ZMx1vFBbchWqE6ITuiGHA4njNVNzkJ1KdI00Tlj63H5wuAsPWOAmubksK6pVAzUoveFukjBLhXppQp35GYCX3B_0Vvy9Pry_vzWzssx4MmuNxm8mbMLkH9MAmf-kujO5iN9GzWOfJSj_PfAL7jZXEg</recordid><startdate>20140214</startdate><enddate>20140214</enddate><creator>Shlush, Liran I.</creator><creator>Zandi, Sasan</creator><creator>Mitchell, Amanda</creator><creator>Chen, Weihsu Claire</creator><creator>Brandwein, Joseph M.</creator><creator>Gupta, Vikas</creator><creator>Kennedy, James A.</creator><creator>Schimmer, Aaron D.</creator><creator>Schuh, Andre C.</creator><creator>Yee, Karen W.</creator><creator>McLeod, Jessica L.</creator><creator>Doedens, Monica</creator><creator>Medeiros, Jessie J.F.</creator><creator>Marke, Rene</creator><creator>Kim, Hyeoung Joon</creator><creator>Lee, Kwon</creator><creator>McPherson, John D.</creator><creator>Hudson, Thomas J.</creator><creator>Brown, Andrew M.K.</creator><creator>Trinh, Quang M.</creator><creator>Stein, Lincoln D.</creator><creator>Minden, Mark D.</creator><creator>Wang, Jean C.Y.</creator><creator>Dick, John E.</creator><scope>5PM</scope></search><sort><creationdate>20140214</creationdate><title>Identification of pre-leukemic hematopoietic stem cells in acute leukemia</title><author>Shlush, Liran I. ; Zandi, Sasan ; Mitchell, Amanda ; Chen, Weihsu Claire ; Brandwein, Joseph M. ; Gupta, Vikas ; Kennedy, James A. ; Schimmer, Aaron D. ; Schuh, Andre C. ; Yee, Karen W. ; McLeod, Jessica L. ; Doedens, Monica ; Medeiros, Jessie J.F. ; Marke, Rene ; Kim, Hyeoung Joon ; Lee, Kwon ; McPherson, John D. ; Hudson, Thomas J. ; Brown, Andrew M.K. ; Trinh, Quang M. ; Stein, Lincoln D. ; Minden, Mark D. ; Wang, Jean C.Y. ; Dick, John E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmedcentral_primary_oai_pubmedcentral_nih_gov_49919393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shlush, Liran I.</creatorcontrib><creatorcontrib>Zandi, Sasan</creatorcontrib><creatorcontrib>Mitchell, Amanda</creatorcontrib><creatorcontrib>Chen, Weihsu Claire</creatorcontrib><creatorcontrib>Brandwein, Joseph M.</creatorcontrib><creatorcontrib>Gupta, Vikas</creatorcontrib><creatorcontrib>Kennedy, James A.</creatorcontrib><creatorcontrib>Schimmer, Aaron D.</creatorcontrib><creatorcontrib>Schuh, Andre C.</creatorcontrib><creatorcontrib>Yee, Karen W.</creatorcontrib><creatorcontrib>McLeod, Jessica L.</creatorcontrib><creatorcontrib>Doedens, Monica</creatorcontrib><creatorcontrib>Medeiros, Jessie J.F.</creatorcontrib><creatorcontrib>Marke, Rene</creatorcontrib><creatorcontrib>Kim, Hyeoung Joon</creatorcontrib><creatorcontrib>Lee, Kwon</creatorcontrib><creatorcontrib>McPherson, John D.</creatorcontrib><creatorcontrib>Hudson, Thomas J.</creatorcontrib><creatorcontrib>Brown, Andrew M.K.</creatorcontrib><creatorcontrib>Trinh, Quang M.</creatorcontrib><creatorcontrib>Stein, Lincoln D.</creatorcontrib><creatorcontrib>Minden, Mark D.</creatorcontrib><creatorcontrib>Wang, Jean C.Y.</creatorcontrib><creatorcontrib>Dick, John E.</creatorcontrib><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shlush, Liran I.</au><au>Zandi, Sasan</au><au>Mitchell, Amanda</au><au>Chen, Weihsu Claire</au><au>Brandwein, Joseph M.</au><au>Gupta, Vikas</au><au>Kennedy, James A.</au><au>Schimmer, Aaron D.</au><au>Schuh, Andre C.</au><au>Yee, Karen W.</au><au>McLeod, Jessica L.</au><au>Doedens, Monica</au><au>Medeiros, Jessie J.F.</au><au>Marke, Rene</au><au>Kim, Hyeoung Joon</au><au>Lee, Kwon</au><au>McPherson, John D.</au><au>Hudson, Thomas J.</au><au>Brown, Andrew M.K.</au><au>Trinh, Quang M.</au><au>Stein, Lincoln D.</au><au>Minden, Mark D.</au><au>Wang, Jean C.Y.</au><au>Dick, John E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of pre-leukemic hematopoietic stem cells in acute leukemia</atitle><jtitle>Nature (London)</jtitle><date>2014-02-14</date><risdate>2014</risdate><volume>506</volume><issue>7488</issue><spage>328</spage><epage>333</epage><pages>328-333</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>In acute myeloid leukemia (AML), the cell of origin, nature and biological consequences of initiating lesions and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukemic phase. Here, highly purified hematopoietic stem cells (HSC), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent
DNMT3a
mutations (
DNMT3a
mut
) at high allele frequency, but without coincident
NPM1
mutations (
NPM1c
) present in AML blasts.
DNMT3a
mut
-bearing HSC exhibited multilineage repopulation advantage over non-mutated HSC in xenografts, establishing their identity as pre-leukemic-HSC (preL-HSC). preL-HSC were found in remission samples indicating that they survive chemotherapy. Thus
DNMT3a
mut
arises early in AML evolution, likely in HSC, leading to a clonally expanded pool of preL-HSC from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.</abstract><pmid>24522528</pmid><doi>10.1038/nature13038</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2014-02, Vol.506 (7488), p.328-333 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4991939 |
| source | Nature; Alma/SFX Local Collection |
| title | Identification of pre-leukemic hematopoietic stem cells in acute leukemia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-22T06%3A07%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmedcentral&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20of%20pre-leukemic%20hematopoietic%20stem%20cells%20in%20acute%20leukemia&rft.jtitle=Nature%20(London)&rft.au=Shlush,%20Liran%20I.&rft.date=2014-02-14&rft.volume=506&rft.issue=7488&rft.spage=328&rft.epage=333&rft.pages=328-333&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/nature13038&rft_dat=%3Cpubmedcentral%3Epubmedcentral_primary_oai_pubmedcentral_nih_gov_4991939%3C/pubmedcentral%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/24522528&rfr_iscdi=true |