Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia

Masayuki Umeda; Jing Ma; Benjamin J. Huang; Kohei Hagiwara; Tamara Westover; Sherif Abdelhamed; Juan M. Barajas; Melvin E. Thomas; Michael P. Walsh; Guangchun Song; Liqing Tian; Yanling Liu; Xiaolong Chen; Pandurang Kolekar; Quang Tran; Scott G. Foy; Jamie L. Maciaszek; Andrew B. Kleist; Amanda R. Leonti; Bengsheng Ju; John Easton; Huiyun Wu; Virginia Valentine; Marcus B. Valentine; Yen Chun Liu; Rhonda E. Ries; Jenny L. Smith; Evan Parganas; Ilaria Iacobucci; Ryan Hiltenbrand; Jonathan Miller; Jason R. Myers; Evadnie Rampersaud; Delaram Rahbarinia; Michael Rusch; Gang Wu; Hiroto Inaba; Yi Cheng Wang; Todd A. Alonzo; James R. Downing; Charles G. Mullighan; Stanley Pounds; M. Madan Babu; Jinghui Zhang; Jeffrey E. Rubnitz; Soheil Meshinchi; Xiaotu Ma; Jeffery M. Klco

doi:10.1158/2643-3230.BCD-21-0160

Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia

Masayuki Umeda, Jing Ma, Benjamin J. Huang, Kohei Hagiwara, Tamara Westover, Sherif Abdelhamed, Juan M. Barajas, Melvin E. Thomas, Michael P. Walsh, Guangchun Song, Liqing Tian, Yanling Liu, Xiaolong Chen, Pandurang Kolekar, Quang Tran, Scott G. Foy, Jamie L. Maciaszek, Andrew B. Kleist, Amanda R. Leonti, Bengsheng JuJohn Easton, Huiyun Wu, Virginia Valentine, Marcus B. Valentine, Yen Chun Liu, Rhonda E. Ries, Jenny L. Smith, Evan Parganas, Ilaria Iacobucci, Ryan Hiltenbrand, Jonathan Miller, Jason R. Myers, Evadnie Rampersaud, Delaram Rahbarinia, Michael Rusch, Gang Wu, Hiroto Inaba, Yi Cheng Wang, Todd A. Alonzo, James R. Downing, Charles G. Mullighan, Stanley Pounds, M. Madan Babu, Jinghui Zhang, Jeffrey E. Rubnitz, Soheil Meshinchi, Xiaotu Ma, Jeffery M. Klco

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

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Abstract

The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML.

Original language	English (US)
Pages (from-to)	194-207
Number of pages	14
Journal	Blood cancer discovery
Volume	3
Issue number	3
DOIs	https://doi.org/10.1158/2643-3230.BCD-21-0160
State	Published - May 1 2022
Externally published	Yes

ASJC Scopus subject areas

General Medicine

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Umeda, M., Ma, J., Huang, B. J., Hagiwara, K., Westover, T., Abdelhamed, S., Barajas, J. M., Thomas, M. E., Walsh, M. P., Song, G., Tian, L., Liu, Y., Chen, X., Kolekar, P., Tran, Q., Foy, S. G., Maciaszek, J. L., Kleist, A. B., Leonti, A. R., ... Klco, J. M. (2022). Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia. Blood cancer discovery, 3(3), 194-207. https://doi.org/10.1158/2643-3230.BCD-21-0160

Umeda, M, Ma, J, Huang, BJ, Hagiwara, K, Westover, T, Abdelhamed, S, Barajas, JM, Thomas, ME, Walsh, MP, Song, G, Tian, L, Liu, Y, Chen, X, Kolekar, P, Tran, Q, Foy, SG, Maciaszek, JL, Kleist, AB, Leonti, AR, Ju, B, Easton, J, Wu, H, Valentine, V, Valentine, MB, Liu, YC, Ries, RE, Smith, JL, Parganas, E, Iacobucci, I, Hiltenbrand, R, Miller, J, Myers, JR, Rampersaud, E, Rahbarinia, D, Rusch, M, Wu, G, Inaba, H, Wang, YC, Alonzo, TA, Downing, JR, Mullighan, CG, Pounds, S, Babu, MM, Zhang, J, Rubnitz, JE, Meshinchi, S, Ma, X & Klco, JM 2022, 'Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia', Blood cancer discovery, vol. 3, no. 3, pp. 194-207. https://doi.org/10.1158/2643-3230.BCD-21-0160

@article{29ca6e275f104f17a0c28599b338cc70,

title = "Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia",

abstract = "The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML.",

author = "Masayuki Umeda and Jing Ma and Huang, {Benjamin J.} and Kohei Hagiwara and Tamara Westover and Sherif Abdelhamed and Barajas, {Juan M.} and Thomas, {Melvin E.} and Walsh, {Michael P.} and Guangchun Song and Liqing Tian and Yanling Liu and Xiaolong Chen and Pandurang Kolekar and Quang Tran and Foy, {Scott G.} and Maciaszek, {Jamie L.} and Kleist, {Andrew B.} and Leonti, {Amanda R.} and Bengsheng Ju and John Easton and Huiyun Wu and Virginia Valentine and Valentine, {Marcus B.} and Liu, {Yen Chun} and Ries, {Rhonda E.} and Smith, {Jenny L.} and Evan Parganas and Ilaria Iacobucci and Ryan Hiltenbrand and Jonathan Miller and Myers, {Jason R.} and Evadnie Rampersaud and Delaram Rahbarinia and Michael Rusch and Gang Wu and Hiroto Inaba and Wang, {Yi Cheng} and Alonzo, {Todd A.} and Downing, {James R.} and Mullighan, {Charles G.} and Stanley Pounds and Babu, {M. Madan} and Jinghui Zhang and Rubnitz, {Jeffrey E.} and Soheil Meshinchi and Xiaotu Ma and Klco, {Jeffery M.}",

note = "Publisher Copyright: {\textcopyright}2022The Authors; Published by the American Association for Cancer Research.",

year = "2022",

month = may,

day = "1",

doi = "10.1158/2643-3230.BCD-21-0160",

language = "English (US)",

volume = "3",

pages = "194--207",

journal = "Blood cancer discovery",

issn = "2643-3230",

number = "3",

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TY - JOUR

T1 - Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia

AU - Umeda, Masayuki

AU - Ma, Jing

AU - Huang, Benjamin J.

AU - Hagiwara, Kohei

AU - Westover, Tamara

AU - Abdelhamed, Sherif

AU - Barajas, Juan M.

AU - Thomas, Melvin E.

AU - Walsh, Michael P.

AU - Song, Guangchun

AU - Tian, Liqing

AU - Liu, Yanling

AU - Chen, Xiaolong

AU - Kolekar, Pandurang

AU - Tran, Quang

AU - Foy, Scott G.

AU - Maciaszek, Jamie L.

AU - Kleist, Andrew B.

AU - Leonti, Amanda R.

AU - Ju, Bengsheng

AU - Easton, John

AU - Wu, Huiyun

AU - Valentine, Virginia

AU - Valentine, Marcus B.

AU - Liu, Yen Chun

AU - Ries, Rhonda E.

AU - Smith, Jenny L.

AU - Parganas, Evan

AU - Iacobucci, Ilaria

AU - Hiltenbrand, Ryan

AU - Miller, Jonathan

AU - Myers, Jason R.

AU - Rampersaud, Evadnie

AU - Rahbarinia, Delaram

AU - Rusch, Michael

AU - Wu, Gang

AU - Inaba, Hiroto

AU - Wang, Yi Cheng

AU - Alonzo, Todd A.

AU - Downing, James R.

AU - Mullighan, Charles G.

AU - Pounds, Stanley

AU - Babu, M. Madan

AU - Zhang, Jinghui

AU - Rubnitz, Jeffrey E.

AU - Meshinchi, Soheil

AU - Ma, Xiaotu

AU - Klco, Jeffery M.

PY - 2022/5/1

Y1 - 2022/5/1

N2 - The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML.

AB - The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML.

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U2 - 10.1158/2643-3230.BCD-21-0160

DO - 10.1158/2643-3230.BCD-21-0160

M3 - Article

C2 - 35176137

AN - SCOPUS:85131454158

SN - 2643-3230

VL - 3

SP - 194

EP - 207

JO - Blood cancer discovery

JF - Blood cancer discovery

IS - 3

ER -

Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia

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