An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia

Tanja A. Gruber; Amanda Larson Gedman; Jinghui Zhang; Cary S. Koss; Suresh Marada; Huy Q. Ta; Shann Ching Chen; Xiaoping Su; Stacey K. Ogden; Jinjun Dang; Gang Wu; Vedant Gupta; Anna K. Andersson; Stanley Pounds; Lei Shi; John Easton; Michael I. Barbato; Heather L. Mulder; Jayanthi Manne; Jianmin Wang; Michael Rusch; Swati Ranade; Ramapriya Ganti; Matthew Parker; Jing Ma; Ina Radtke; Li Ding; Giovanni Cazzaniga; Andrea Biondi; Steven M. Kornblau; Farhad Ravandi; Hagop Kantarjian; Stephen D. Nimer; Konstanze Döhner; Hartmut Döhner; Timothy J. Ley; Paola Ballerini; Sheila Shurtleff; Daisuke Tomizawa; Souichi Adachi; Yasuhide Hayashi; Akio Tawa; Lee Yung Shih; Der Cherng Liang; Jeffrey E. Rubnitz; Ching Hon Pui; Elaine R. Mardis; Richard K. Wilson; James R. Downing

doi:10.1016/j.ccr.2012.10.007

An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia

Tanja A. Gruber, Amanda Larson Gedman, Jinghui Zhang, Cary S. Koss, Suresh Marada, Huy Q. Ta, Shann Ching Chen, Xiaoping Su, Stacey K. Ogden, Jinjun Dang, Gang Wu, Vedant Gupta, Anna K. Andersson, Stanley Pounds, Lei Shi, John Easton, Michael I. Barbato, Heather L. Mulder, Jayanthi Manne, Jianmin WangMichael Rusch, Swati Ranade, Ramapriya Ganti, Matthew Parker, Jing Ma, Ina Radtke, Li Ding, Giovanni Cazzaniga, Andrea Biondi, Steven M. Kornblau, Farhad Ravandi, Hagop Kantarjian, Stephen D. Nimer, Konstanze Döhner, Hartmut Döhner, Timothy J. Ley, Paola Ballerini, Sheila Shurtleff, Daisuke Tomizawa, Souichi Adachi, Yasuhide Hayashi, Akio Tawa, Lee Yung Shih, Der Cherng Liang, Jeffrey E. Rubnitz, Ching Hon Pui, Elaine R. Mardis, Richard K. Wilson, James R. Downing

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Abstract

To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.

Original language	English
Pages (from-to)	683-697
Number of pages	15
Journal	Cancer Cell
Volume	22
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2012.10.007
State	Published - Nov 13 2012

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10.1016/j.ccr.2012.10.007

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Gruber, T. A., Larson Gedman, A., Zhang, J., Koss, C. S., Marada, S., Ta, H. Q., Chen, S. C., Su, X., Ogden, S. K., Dang, J., Wu, G., Gupta, V., Andersson, A. K., Pounds, S., Shi, L., Easton, J., Barbato, M. I., Mulder, H. L., Manne, J., ... Downing, J. R. (2012). An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia. Cancer Cell, 22(5), 683-697. https://doi.org/10.1016/j.ccr.2012.10.007

@article{93f81fb2c8764621a01393e95d75eb5d,

title = "An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia",

abstract = "To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.",

author = "Gruber, {Tanja A.} and {Larson Gedman}, Amanda and Jinghui Zhang and Koss, {Cary S.} and Suresh Marada and Ta, {Huy Q.} and Chen, {Shann Ching} and Xiaoping Su and Ogden, {Stacey K.} and Jinjun Dang and Gang Wu and Vedant Gupta and Andersson, {Anna K.} and Stanley Pounds and Lei Shi and John Easton and Barbato, {Michael I.} and Mulder, {Heather L.} and Jayanthi Manne and Jianmin Wang and Michael Rusch and Swati Ranade and Ramapriya Ganti and Matthew Parker and Jing Ma and Ina Radtke and Li Ding and Giovanni Cazzaniga and Andrea Biondi and Kornblau, {Steven M.} and Farhad Ravandi and Hagop Kantarjian and Nimer, {Stephen D.} and Konstanze D{\"o}hner and Hartmut D{\"o}hner and Ley, {Timothy J.} and Paola Ballerini and Sheila Shurtleff and Daisuke Tomizawa and Souichi Adachi and Yasuhide Hayashi and Akio Tawa and Shih, {Lee Yung} and Liang, {Der Cherng} and Rubnitz, {Jeffrey E.} and Pui, {Ching Hon} and Mardis, {Elaine R.} and Wilson, {Richard K.} and Downing, {James R.}",

note = "Funding Information: The authors would like to specifically thank Joy Nakitandwe for critical input and discussions, Susana Raimondi for review of cytogenetics, Matt Stine for assistance with data deposition, Bill Pappas and Scott Malone for support of the information technology infrastructure, and the staff of Tissue Resources Laboratory, Flow Cytometry and Cell Sorting Core, the Hartwell Center for Biotechnology and Bioinformatics of St Jude Children{\textquoteright}s Research Hospital, and Emily Dolezale for assistance in sample procurement at Memorial Sloan Kettering Cancer Center. This work was supported by grants from the National Institutes of Health (Cancer Center Support Grant P30 CA021765), the Eric Trump Foundation, a Leukemia & Lymphoma Society Specialized Center of Research Grant LLS7015, and the American Lebanese Syrian Associated Charities (ALSAC) of St Jude Children{\textquoteright}s Research Hospital. ",

year = "2012",

month = nov,

day = "13",

doi = "10.1016/j.ccr.2012.10.007",

language = "English",

volume = "22",

pages = "683--697",

journal = "Cancer Cell",

issn = "1535-6108",

number = "5",

}

Gruber, TA, Larson Gedman, A, Zhang, J, Koss, CS, Marada, S, Ta, HQ, Chen, SC, Su, X, Ogden, SK, Dang, J, Wu, G, Gupta, V, Andersson, AK, Pounds, S, Shi, L, Easton, J, Barbato, MI, Mulder, HL, Manne, J, Wang, J, Rusch, M, Ranade, S, Ganti, R, Parker, M, Ma, J, Radtke, I, Ding, L, Cazzaniga, G, Biondi, A, Kornblau, SM, Ravandi, F, Kantarjian, H, Nimer, SD, Döhner, K, Döhner, H, Ley, TJ, Ballerini, P, Shurtleff, S, Tomizawa, D, Adachi, S, Hayashi, Y, Tawa, A, Shih, LY, Liang, DC, Rubnitz, JE, Pui, CH, Mardis, ER, Wilson, RK & Downing, JR 2012, 'An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia', Cancer Cell, vol. 22, no. 5, pp. 683-697. https://doi.org/10.1016/j.ccr.2012.10.007

TY - JOUR

T1 - An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia

AU - Gruber, Tanja A.

AU - Larson Gedman, Amanda

AU - Zhang, Jinghui

AU - Koss, Cary S.

AU - Marada, Suresh

AU - Ta, Huy Q.

AU - Chen, Shann Ching

AU - Su, Xiaoping

AU - Ogden, Stacey K.

AU - Dang, Jinjun

AU - Wu, Gang

AU - Gupta, Vedant

AU - Andersson, Anna K.

AU - Pounds, Stanley

AU - Shi, Lei

AU - Easton, John

AU - Barbato, Michael I.

AU - Mulder, Heather L.

AU - Manne, Jayanthi

AU - Wang, Jianmin

AU - Rusch, Michael

AU - Ranade, Swati

AU - Ganti, Ramapriya

AU - Parker, Matthew

AU - Ma, Jing

AU - Radtke, Ina

AU - Ding, Li

AU - Cazzaniga, Giovanni

AU - Biondi, Andrea

AU - Kornblau, Steven M.

AU - Ravandi, Farhad

AU - Kantarjian, Hagop

AU - Nimer, Stephen D.

AU - Döhner, Konstanze

AU - Döhner, Hartmut

AU - Ley, Timothy J.

AU - Ballerini, Paola

AU - Shurtleff, Sheila

AU - Tomizawa, Daisuke

AU - Adachi, Souichi

AU - Hayashi, Yasuhide

AU - Tawa, Akio

AU - Shih, Lee Yung

AU - Liang, Der Cherng

AU - Rubnitz, Jeffrey E.

AU - Pui, Ching Hon

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Downing, James R.

N1 - Funding Information: The authors would like to specifically thank Joy Nakitandwe for critical input and discussions, Susana Raimondi for review of cytogenetics, Matt Stine for assistance with data deposition, Bill Pappas and Scott Malone for support of the information technology infrastructure, and the staff of Tissue Resources Laboratory, Flow Cytometry and Cell Sorting Core, the Hartwell Center for Biotechnology and Bioinformatics of St Jude Children’s Research Hospital, and Emily Dolezale for assistance in sample procurement at Memorial Sloan Kettering Cancer Center. This work was supported by grants from the National Institutes of Health (Cancer Center Support Grant P30 CA021765), the Eric Trump Foundation, a Leukemia & Lymphoma Society Specialized Center of Research Grant LLS7015, and the American Lebanese Syrian Associated Charities (ALSAC) of St Jude Children’s Research Hospital.

PY - 2012/11/13

Y1 - 2012/11/13

N2 - To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.

AB - To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.

UR - http://www.scopus.com/inward/record.url?scp=84869009858&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2012.10.007

DO - 10.1016/j.ccr.2012.10.007

M3 - Article

C2 - 23153540

AN - SCOPUS:84869009858

SN - 1535-6108

VL - 22

SP - 683

EP - 697

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia

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