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

St Jude Children´s Research Hospital, Memphis

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

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
Publication status	Published - 2012 Nov 13
Externally published	Yes

Bibliographical note

Subject classification (UKÄ)

Cancer and Oncology
Basic Medicine

Free keywords

Animals
Bone Morphogenetic Proteins/metabolism
Child
Chromosome Inversion
Chromosomes, Human, Pair 16
Drosophila/genetics
Gene Expression Profiling
Humans
Kruppel-Like Transcription Factors/genetics
Leukemia, Megakaryoblastic, Acute/classification
Mice
Oncogene Proteins, Fusion/genetics
Prognosis
Recombinant Fusion Proteins/genetics
Repressor Proteins/genetics
Sequence Analysis, RNA
Signal Transduction
Tumor Suppressor Proteins/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccr.2012.10.007

http://europepmc.org/abstract/MED/23153540

Cite this

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

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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.",

keywords = "Animals, Bone Morphogenetic Proteins/metabolism, Child, Chromosome Inversion, Chromosomes, Human, Pair 16, Drosophila/genetics, Gene Expression Profiling, Humans, Kruppel-Like Transcription Factors/genetics, Leukemia, Megakaryoblastic, Acute/classification, Mice, Oncogene Proteins, Fusion/genetics, Prognosis, Recombinant Fusion Proteins/genetics, Repressor Proteins/genetics, Sequence Analysis, RNA, Signal Transduction, Tumor Suppressor Proteins/genetics",

author = "Gruber, {Tanja A} and {Larson Gedman}, Amanda and Jinghui Zhang and Koss, {Cary S} and Suresh Marada and Ta, {Huy Q} and Shann-Ching Chen 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 Lee-Yung Shih and Der-Cherng Liang and Rubnitz, {Jeffrey E} and Ching-Hon Pui and Mardis, {Elaine R} and Wilson, {Richard K} and Downing, {James R}",

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 = "1878-3686",

publisher = "Cell Press",

number = "5",

}

Gruber, TA, Larson Gedman, A, Zhang, J, Koss, CS, Marada, S, Ta, HQ, Chen, S-C, 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, L-Y, Liang, D-C, Rubnitz, JE, Pui, C-H, 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

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.

KW - Animals

KW - Bone Morphogenetic Proteins/metabolism

KW - Child

KW - Chromosome Inversion

KW - Chromosomes, Human, Pair 16

KW - Drosophila/genetics

KW - Gene Expression Profiling

KW - Humans

KW - Kruppel-Like Transcription Factors/genetics

KW - Leukemia, Megakaryoblastic, Acute/classification

KW - Mice

KW - Oncogene Proteins, Fusion/genetics

KW - Prognosis

KW - Recombinant Fusion Proteins/genetics

KW - Repressor Proteins/genetics

KW - Sequence Analysis, RNA

KW - Signal Transduction

KW - Tumor Suppressor Proteins/genetics

U2 - 10.1016/j.ccr.2012.10.007

DO - 10.1016/j.ccr.2012.10.007

M3 - Article

C2 - 23153540

SN - 1878-3686

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

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

Access to Document

Fingerprint

Cite this