Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia

被引:34
作者
Bertrums, Eline J. M. [1 ,2 ,3 ]
Smith, Jenny L. [4 ]
Harmon, Lauren [5 ]
Ries, Rhonda E. [4 ]
Wang, Yi-Cheng J. [6 ]
Alonzo, Todd A. [6 ,7 ]
Menssen, Andrew J. [8 ]
Chisholm, Karen M. [9 ]
Leonti, Amanda R. [4 ]
Tarlock, Katherine [4 ,10 ]
Ostronoff, Fabiana [11 ]
Pogosova-Agadjanyan, Era L. [4 ]
Kaspers, Gertjan J. L. [1 ,12 ,13 ]
Hasle, Henrik [14 ]
Dworzak, Michael [15 ,16 ]
Walter, Christiane [17 ]
Muehlegger, Nora [15 ]
Morerio, Cristina [18 ]
Pardo, Laura [8 ]
Hirsch, Betsy [19 ]
Raimondi, Susana [19 ]
Cooper, Todd M. [10 ]
Aplenc, Richard [20 ]
Gamis, Alan S. [21 ]
Kolb, Edward A. [22 ]
Farrar, Jason E. [23 ]
Stirewalt, Derek [4 ]
Ma, Xiaotu [24 ]
Shaw, Tim I. [24 ]
Furlan, Scott N. [4 ]
Brodersen, Lisa Eidenschink [8 ]
Loken, Michael R. [8 ]
Heuvel-Eibrink, Marry M. van den [25 ]
Zwaan, C. Michel [1 ,2 ]
Triche, Timothy J. [5 ,6 ,26 ]
Goemans, Bianca F. [1 ]
Meshinchi, Soheil [4 ,7 ,10 ]
机构
[1] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands
[2] Erasmus MC, Sophia Childrens Hosp, Dept Pediat Oncol Hematol, Rotterdam, Netherlands
[3] Oncode Inst, Utrecht, Netherlands
[4] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98109 USA
[5] Andel Inst, Dept Epigenet, Grand Rapids, MI USA
[6] Univ Southern Calif, Dept Translat Genom, Los Angeles, CA USA
[7] Childrens Oncol Grp, Monrovia, CA 91016 USA
[8] Hematologics Inc, Seattle, WA USA
[9] Seattle Childrens Hosp, Dept Labs, Seattle, WA USA
[10] Seattle Childrens Hosp, Div Hematol & Oncol, Seattle, WA 98105 USA
[11] Intermt Blood & Marrow Transplant & Acute Leukemia, Intermt Healthcare, Salt Lake City, UT USA
[12] Vrije Univ Amsterdam, Emma Childrens Hosp, Amsterdam UMC, Pediat Oncol, Amsterdam, Netherlands
[13] Dutch Childhood Oncol Grp, The Hague, Netherlands
[14] Aarhus Univ Hosp, Dept Pediat, Aarhus, Denmark
[15] Med Univ Vienna, Childrens Canc Res Inst, Vienna, Austria
[16] Med Univ Vienna, Dept Pediat, St Anna Kinderspital, Vienna, Austria
[17] Univ Hosp Essen, Dept Pediat Hematol & Oncol, Essen, Germany
[18] IRCCS Ist Giannina Gaslini, Lab Human Genet, Genoa, Italy
[19] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN USA
[20] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Div Oncol, Philadelphia, PA USA
[21] Childrens Mercy Kansas City, Div Hematol Oncol, Kansas City, MO USA
[22] Nemours Alfred I duPont Hosp Children, Wilmington, DE USA
[23] Univ Arkansas Med Sci, Little Rock, AR USA
[24] St Jude Childrens Res Hosp, Computat Biol Dept, Memphis, TN USA
[25] Univ Utrecht, Utrecht, Netherlands
[26] Michigan State Univ, Dept Pediat, Coll Human Med, Grand Rapids, MI USA
关键词
ACUTE MEGAKARYOBLASTIC LEUKEMIA; CHILDRENS-ONCOLOGY-GROUP; NUP98; GENE; EXPRESSION; AML; TRIAL; CHEMOTHERAPY; CYTARABINE; OUTCOMES;
D O I
10.3324/haematol.2022.281653
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
NUP98 fusions comprise a family of rare recurrent alterations in AML, associated with adverse outcomes. In order to define the underlying biology and clinical implications of this family of fusions, we performed comprehensive transcriptome, epigenome, and immunophenotypic profiling of 2,235 children and young adults with AML and identified 160 NUP98 rearrangements (7.2%), including 108 NUP98-NSD1 (4.8%), 32 NUP98-KDM5A (1.4%) and 20 NUP98-X cases (0.9%) with 13 different fusion partners. Fusion partners defined disease characteristics and biology; patients with NUP98-NSD1 or NUP98-KDM5A had distinct immunophenotypic, transcriptomic, and epigenomic profiles. Unlike the two most prevalent NUP98 fusions, NUP98-X variants are typically not cryptic. Furthermore, NUP98-X cases are associated with WT1 mutations, and have epigenomic profiles that resemble either NUP98-NSD1 or NUP98-KDM5A. Cooperating FLT3-ITD and WT1 mutations define NUP98-NSD1, and chromosome 13 aberrations are highly enriched in NUP98-KDM5A. Importantly, we demonstrate that NUP98 fusions portend dismal overall survival, with the noteworthy exception of patients bearing abnormal chromosome 13 (clinicaltrials gov. Identifiers: NCT00002798, NCT00070174, NCT00372593, NCT01371981).
引用
收藏
页码:2044 / 2058
页数:15
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