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

Eline J.M. Bertrums; Jenny L. Smith; Lauren Harmon; Rhonda E. Ries; Yi Cheng J. Wang; Todd A. Alonzo; Andrew J. Menssen; Karen M. Chisholm; Amanda R. Leonti; Katherine Tarlock; Fabiana Ostronoff; Era L. Pogosova-Agadjanyan; Gertjan J.L. Kaspers; Henrik Hasle; Michael Dworzak; Christiane Walter; Nora Muhlegger; Cristina Morerio; Laura Pardo; Betsy Hirsch; Susana Raimondi; Todd M. Cooper; Richard Aplenc; Alan S. Gamis; Edward A. Kolb; Jason E. Farrar; Derek Stirewalt; Xiaotu Ma; Tim I. Shaw; Scott N. Furlan; Lisa Eidenschink Brodersen; Michael R. Loken; Marry M. Van den Heuvel-Eibrink; C. Michel Zwaan; Timothy J. Triche; Bianca F. Goemans; Soheil Meshinchi

doi:10.3324/haematol.2022.281653

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

Eline J.M. Bertrums^*
, Jenny L. Smith
, Lauren Harmon
, Rhonda E. Ries
, Yi Cheng J. Wang
, Todd A. Alonzo
, Andrew J. Menssen
, Karen M. Chisholm
, Amanda R. Leonti
, Katherine Tarlock
, Fabiana Ostronoff
, Era L. Pogosova-Agadjanyan
, Gertjan J.L. Kaspers
, Henrik Hasle
, Michael Dworzak
, Christiane Walter
, Nora Muhlegger
, Cristina Morerio
, Laura Pardo
, Betsy Hirsch

Susana Raimondi, Todd M. Cooper, Richard Aplenc, Alan S. Gamis, Edward A. Kolb, Jason E. Farrar, Derek Stirewalt, Xiaotu Ma, Tim I. Shaw, Scott N. Furlan, Lisa Eidenschink Brodersen, Michael R. Loken, Marry M. Van den Heuvel-Eibrink, C. Michel Zwaan, Timothy J. Triche, Bianca F. Goemans, Soheil Meshinchi^*

^*Corresponding author for this work

Pediatrics

Fred Hutchinson Cancer Research Center
Van Andel Institute
University of Southern California
HematoLogics Inc
University of Washington
Primary Children's Medical Center
Princess Máxima Center for Pediatric Oncology
Aarhus University Hospital
Medical University of Vienna
University Hospital Essen
IRCCS Istituto Giannina Gaslini - Genova
St. Jude Children Research Hospital
Children's Hospital of Philadelphia
Children’s Mercy Kansas City
Alfred I. duPont Hospital for Children
University of Arkansas for Medical Sciences

Research output: Contribution to journal › Article › Academic › peer-review

61 Citations (Scopus)

97 Downloads (Pure)

Abstract

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).

Original language	English
Pages (from-to)	2044-2058
Number of pages	15
Journal	Haematologica
Volume	108
Issue number	8
DOIs	https://doi.org/10.3324/haematol.2022.281653
Publication status	Published - Aug 2023

Bibliographical note

Funding Information:
This work was supported by the following NIH/NCI/NCTN grant awards: RO1CA190661, R01CA160872, R01AI171984, U10CA180888, U10CA180819, and U24CA196175, U10CA180886, U10CA180899, St. Baldricks Foundation, the Rally Foundation, and the Michelle Lunn Hope Foundation. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
©2023 Ferrata Storti Foundation.

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Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemiaFinal published version, 3.29 MBLicence: CC BY-NC

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Bertrums, E. J. M., Smith, J. L., Harmon, L., Ries, R. E., Wang, Y. C. J., Alonzo, T. A., Menssen, A. J., Chisholm, K. M., Leonti, A. R., Tarlock, K., Ostronoff, F., Pogosova-Agadjanyan, E. L., Kaspers, G. J. L., Hasle, H., Dworzak, M., Walter, C., Muhlegger, N., Morerio, C., Pardo, L., ... Meshinchi, S. (2023). Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia. Haematologica, 108(8), 2044-2058. https://doi.org/10.3324/haematol.2022.281653

@article{ae2faa052531425799436a1e06330d05,

title = "Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia",

abstract = "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).",

author = "Bertrums, \{Eline J.M.\} and Smith, \{Jenny L.\} and Lauren Harmon and Ries, \{Rhonda E.\} and Wang, \{Yi Cheng J.\} and Alonzo, \{Todd A.\} and Menssen, \{Andrew J.\} and Chisholm, \{Karen M.\} and Leonti, \{Amanda R.\} and Katherine Tarlock and Fabiana Ostronoff and Pogosova-Agadjanyan, \{Era L.\} and Kaspers, \{Gertjan J.L.\} and Henrik Hasle and Michael Dworzak and Christiane Walter and Nora Muhlegger and Cristina Morerio and Laura Pardo and Betsy Hirsch and Susana Raimondi and Cooper, \{Todd M.\} and Richard Aplenc and Gamis, \{Alan S.\} and Kolb, \{Edward A.\} and Farrar, \{Jason E.\} and Derek Stirewalt and Xiaotu Ma and Shaw, \{Tim I.\} and Furlan, \{Scott N.\} and Brodersen, \{Lisa Eidenschink\} and Loken, \{Michael R.\} and \{Van den Heuvel-Eibrink\}, \{Marry M.\} and Zwaan, \{C. Michel\} and Triche, \{Timothy J.\} and Goemans, \{Bianca F.\} and Soheil Meshinchi",

note = "Funding Information: This work was supported by the following NIH/NCI/NCTN grant awards: RO1CA190661, R01CA160872, R01AI171984, U10CA180888, U10CA180819, and U24CA196175, U10CA180886, U10CA180899, St. Baldricks Foundation, the Rally Foundation, and the Michelle Lunn Hope Foundation. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright}2023 Ferrata Storti Foundation.",

year = "2023",

month = aug,

doi = "10.3324/haematol.2022.281653",

language = "English",

volume = "108",

pages = "2044--2058",

number = "8",

}

Bertrums, EJM, Smith, JL, Harmon, L, Ries, RE, Wang, YCJ, Alonzo, TA, Menssen, AJ, Chisholm, KM, Leonti, AR, Tarlock, K, Ostronoff, F, Pogosova-Agadjanyan, EL, Kaspers, GJL, Hasle, H, Dworzak, M, Walter, C, Muhlegger, N, Morerio, C, Pardo, L, Hirsch, B, Raimondi, S, Cooper, TM, Aplenc, R, Gamis, AS, Kolb, EA, Farrar, JE, Stirewalt, D, Ma, X, Shaw, TI, Furlan, SN, Brodersen, LE, Loken, MR, Van den Heuvel-Eibrink, MM, Zwaan, CM, Triche, TJ, Goemans, BF & Meshinchi, S 2023, 'Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia', Haematologica, vol. 108, no. 8, pp. 2044-2058. https://doi.org/10.3324/haematol.2022.281653

TY - JOUR

T1 - Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia

AU - Bertrums, Eline J.M.

AU - Smith, Jenny L.

AU - Harmon, Lauren

AU - Ries, Rhonda E.

AU - Wang, Yi Cheng J.

AU - Alonzo, Todd A.

AU - Menssen, Andrew J.

AU - Chisholm, Karen M.

AU - Leonti, Amanda R.

AU - Tarlock, Katherine

AU - Ostronoff, Fabiana

AU - Pogosova-Agadjanyan, Era L.

AU - Kaspers, Gertjan J.L.

AU - Hasle, Henrik

AU - Dworzak, Michael

AU - Walter, Christiane

AU - Muhlegger, Nora

AU - Morerio, Cristina

AU - Pardo, Laura

AU - Hirsch, Betsy

AU - Raimondi, Susana

AU - Cooper, Todd M.

AU - Aplenc, Richard

AU - Gamis, Alan S.

AU - Kolb, Edward A.

AU - Farrar, Jason E.

AU - Stirewalt, Derek

AU - Ma, Xiaotu

AU - Shaw, Tim I.

AU - Furlan, Scott N.

AU - Brodersen, Lisa Eidenschink

AU - Loken, Michael R.

AU - Van den Heuvel-Eibrink, Marry M.

AU - Zwaan, C. Michel

AU - Triche, Timothy J.

AU - Goemans, Bianca F.

AU - Meshinchi, Soheil

N1 - Funding Information: This work was supported by the following NIH/NCI/NCTN grant awards: RO1CA190661, R01CA160872, R01AI171984, U10CA180888, U10CA180819, and U24CA196175, U10CA180886, U10CA180899, St. Baldricks Foundation, the Rally Foundation, and the Michelle Lunn Hope Foundation. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: ©2023 Ferrata Storti Foundation.

PY - 2023/8

Y1 - 2023/8

N2 - 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).

AB - 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).

UR - https://www.scopus.com/pages/publications/85161878773

U2 - 10.3324/haematol.2022.281653

DO - 10.3324/haematol.2022.281653

M3 - Article

C2 - 36815378

AN - SCOPUS:85161878773

SN - 0390-6078

VL - 108

SP - 2044

EP - 2058

JO - Haematologica

JF - Haematologica

IS - 8

ER -

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

Abstract

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