The genomic landscape of hypodiploid acute lymphoblastic leukemia

Linda Holmfeldt; Lei Wei; Ernesto Diaz-Flores; Michael F Walsh; Jinghui Zhang; Li Ding; Debbie Payne-Turner; Michelle Churchman; Anna Andersson; Shann-Ching Chen; Kelly McCastlain; Jared Becksfort; Jing Ma; Gang Wu; Samir N Patel; Susan L Heatley; Letha A Phillips; Guangchun Song; John Easton; Matthew Parker; Xiang Chen; Michael Rusch; Kristy Boggs; Bhavin Vadodaria; Erin Hedlund; Christina Drenberg; Sharyn D Baker; Deqing Pei; Cheng Cheng; Robert Huether; Charles Lu; Robert S Fulton; Lucinda L Fulton; Yashodhan Tabib; David J Dooling; Kerri Ochoa; Mark Minden; Ian D Lewis; Luen Bik To; Paula Marlton; Andrew W Roberts; Gordana Raca; Wendy Stock; Geoffrey Neale; Hans G Drexler; Ross Alexander Dickins; David W Ellison; Sheila A Shurtleff; Ching-Hon Pui; Raul C Ribeiro; Meenakshi Devidas; Andrew J Carroll; Nyla A Heerema; Brent Wood; Michael J Borowitz; Julie M Gastier-Foster; Susana C Raimondi; Elaine R Mardis; Richard K Wilson; Stephen P Hunger; James R Downing; Mignon Lee-Cheun Loh; Charles G Mullighan

doi:10.1038/ng.2532

The genomic landscape of hypodiploid acute lymphoblastic leukemia

Linda Holmfeldt, Lei Wei, Ernesto Diaz-Flores, Michael F Walsh, Jinghui Zhang, Li Ding, Debbie Payne-Turner, Michelle Churchman, Anna Andersson, Shann-Ching Chen, Kelly McCastlain, Jared Becksfort, Jing Ma, Gang Wu, Samir N Patel, Susan L Heatley, Letha A Phillips, Guangchun Song, John Easton, Matthew ParkerXiang Chen, Michael Rusch, Kristy Boggs, Bhavin Vadodaria, Erin Hedlund, Christina Drenberg, Sharyn D Baker, Deqing Pei, Cheng Cheng, Robert Huether, Charles Lu, Robert S Fulton, Lucinda L Fulton, Yashodhan Tabib, David J Dooling, Kerri Ochoa, Mark Minden, Ian D Lewis, Luen Bik To, Paula Marlton, Andrew W Roberts, Gordana Raca, Wendy Stock, Geoffrey Neale, Hans G Drexler, Ross Alexander Dickins, David W Ellison, Sheila A Shurtleff, Ching-Hon Pui, Raul C Ribeiro, Meenakshi Devidas, Andrew J Carroll, Nyla A Heerema, Brent Wood, Michael J Borowitz, Julie M Gastier-Foster, Susana C Raimondi, Elaine R Mardis, Richard K Wilson, Stephen P Hunger, James R Downing, Mignon Lee-Cheun Loh, Charles G Mullighan

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

412 Citations (Scopus)

Abstract

The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71 ) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13 ). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2 ) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53 ) and RB1 (41 ). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.

Original language	English
Pages (from-to)	242 - 252
Number of pages	11
Journal	Nature Genetics
Volume	45
DOIs	https://doi.org/10.1038/ng.2532
Publication status	Published - 2013
Externally published	Yes

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Holmfeldt, L., Wei, L., Diaz-Flores, E., Walsh, M. F., Zhang, J., Ding, L., Payne-Turner, D., Churchman, M., Andersson, A., Chen, S-C., McCastlain, K., Becksfort, J., Ma, J., Wu, G., Patel, S. N., Heatley, S. L., Phillips, L. A., Song, G., Easton, J., ... Mullighan, C. G. (2013). The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nature Genetics, 45, 242 - 252. https://doi.org/10.1038/ng.2532

Holmfeldt, Linda ; Wei, Lei ; Diaz-Flores, Ernesto ; Walsh, Michael F ; Zhang, Jinghui ; Ding, Li ; Payne-Turner, Debbie ; Churchman, Michelle ; Andersson, Anna ; Chen, Shann-Ching ; McCastlain, Kelly ; Becksfort, Jared ; Ma, Jing ; Wu, Gang ; Patel, Samir N ; Heatley, Susan L ; Phillips, Letha A ; Song, Guangchun ; Easton, John ; Parker, Matthew ; Chen, Xiang ; Rusch, Michael ; Boggs, Kristy ; Vadodaria, Bhavin ; Hedlund, Erin ; Drenberg, Christina ; Baker, Sharyn D ; Pei, Deqing ; Cheng, Cheng ; Huether, Robert ; Lu, Charles ; Fulton, Robert S ; Fulton, Lucinda L ; Tabib, Yashodhan ; Dooling, David J ; Ochoa, Kerri ; Minden, Mark ; Lewis, Ian D ; To, Luen Bik ; Marlton, Paula ; Roberts, Andrew W ; Raca, Gordana ; Stock, Wendy ; Neale, Geoffrey ; Drexler, Hans G ; Dickins, Ross Alexander ; Ellison, David W ; Shurtleff, Sheila A ; Pui, Ching-Hon ; Ribeiro, Raul C ; Devidas, Meenakshi ; Carroll, Andrew J ; Heerema, Nyla A ; Wood, Brent ; Borowitz, Michael J ; Gastier-Foster, Julie M ; Raimondi, Susana C ; Mardis, Elaine R ; Wilson, Richard K ; Hunger, Stephen P ; Downing, James R ; Loh, Mignon Lee-Cheun ; Mullighan, Charles G. / The genomic landscape of hypodiploid acute lymphoblastic leukemia. In: Nature Genetics. 2013 ; Vol. 45. pp. 242 - 252.

@article{12cd4725d6044bbc8911367ae736b46a,

title = "The genomic landscape of hypodiploid acute lymphoblastic leukemia",

abstract = "The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71 ) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13 ). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2 ) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53 ) and RB1 (41 ). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.",

author = "Linda Holmfeldt and Lei Wei and Ernesto Diaz-Flores and Walsh, {Michael F} and Jinghui Zhang and Li Ding and Debbie Payne-Turner and Michelle Churchman and Anna Andersson and Shann-Ching Chen and Kelly McCastlain and Jared Becksfort and Jing Ma and Gang Wu and Patel, {Samir N} and Heatley, {Susan L} and Phillips, {Letha A} and Guangchun Song and John Easton and Matthew Parker and Xiang Chen and Michael Rusch and Kristy Boggs and Bhavin Vadodaria and Erin Hedlund and Christina Drenberg and Baker, {Sharyn D} and Deqing Pei and Cheng Cheng and Robert Huether and Charles Lu and Fulton, {Robert S} and Fulton, {Lucinda L} and Yashodhan Tabib and Dooling, {David J} and Kerri Ochoa and Mark Minden and Lewis, {Ian D} and To, {Luen Bik} and Paula Marlton and Roberts, {Andrew W} and Gordana Raca and Wendy Stock and Geoffrey Neale and Drexler, {Hans G} and Dickins, {Ross Alexander} and Ellison, {David W} and Shurtleff, {Sheila A} and Ching-Hon Pui and Ribeiro, {Raul C} and Meenakshi Devidas and Carroll, {Andrew J} and Heerema, {Nyla A} and Brent Wood and Borowitz, {Michael J} and Gastier-Foster, {Julie M} and Raimondi, {Susana C} and Mardis, {Elaine R} and Wilson, {Richard K} and Hunger, {Stephen P} and Downing, {James R} and Loh, {Mignon Lee-Cheun} and Mullighan, {Charles G}",

year = "2013",

doi = "10.1038/ng.2532",

language = "English",

volume = "45",

pages = "242 -- 252",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

}

Holmfeldt, L, Wei, L, Diaz-Flores, E, Walsh, MF, Zhang, J, Ding, L, Payne-Turner, D, Churchman, M, Andersson, A, Chen, S-C, McCastlain, K, Becksfort, J, Ma, J, Wu, G, Patel, SN, Heatley, SL, Phillips, LA, Song, G, Easton, J, Parker, M, Chen, X, Rusch, M, Boggs, K, Vadodaria, B, Hedlund, E, Drenberg, C, Baker, SD, Pei, D, Cheng, C, Huether, R, Lu, C, Fulton, RS, Fulton, LL, Tabib, Y, Dooling, DJ, Ochoa, K, Minden, M, Lewis, ID, To, LB, Marlton, P, Roberts, AW, Raca, G, Stock, W, Neale, G, Drexler, HG, Dickins, RA, Ellison, DW, Shurtleff, SA, Pui, C-H, Ribeiro, RC, Devidas, M, Carroll, AJ, Heerema, NA, Wood, B, Borowitz, MJ, Gastier-Foster, JM, Raimondi, SC, Mardis, ER, Wilson, RK, Hunger, SP, Downing, JR, Loh, ML-C & Mullighan, CG 2013, 'The genomic landscape of hypodiploid acute lymphoblastic leukemia', Nature Genetics, vol. 45, pp. 242 - 252. https://doi.org/10.1038/ng.2532

The genomic landscape of hypodiploid acute lymphoblastic leukemia. / Holmfeldt, Linda; Wei, Lei; Diaz-Flores, Ernesto; Walsh, Michael F; Zhang, Jinghui; Ding, Li; Payne-Turner, Debbie; Churchman, Michelle; Andersson, Anna; Chen, Shann-Ching; McCastlain, Kelly; Becksfort, Jared; Ma, Jing; Wu, Gang; Patel, Samir N; Heatley, Susan L; Phillips, Letha A; Song, Guangchun; Easton, John; Parker, Matthew; Chen, Xiang; Rusch, Michael; Boggs, Kristy; Vadodaria, Bhavin; Hedlund, Erin; Drenberg, Christina; Baker, Sharyn D; Pei, Deqing; Cheng, Cheng; Huether, Robert; Lu, Charles; Fulton, Robert S; Fulton, Lucinda L; Tabib, Yashodhan; Dooling, David J; Ochoa, Kerri; Minden, Mark; Lewis, Ian D; To, Luen Bik; Marlton, Paula; Roberts, Andrew W; Raca, Gordana; Stock, Wendy; Neale, Geoffrey; Drexler, Hans G; Dickins, Ross Alexander; Ellison, David W; Shurtleff, Sheila A; Pui, Ching-Hon; Ribeiro, Raul C; Devidas, Meenakshi; Carroll, Andrew J; Heerema, Nyla A; Wood, Brent; Borowitz, Michael J; Gastier-Foster, Julie M; Raimondi, Susana C; Mardis, Elaine R; Wilson, Richard K; Hunger, Stephen P; Downing, James R; Loh, Mignon Lee-Cheun; Mullighan, Charles G.

In: Nature Genetics, Vol. 45, 2013, p. 242 - 252.

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

TY - JOUR

T1 - The genomic landscape of hypodiploid acute lymphoblastic leukemia

AU - Holmfeldt, Linda

AU - Wei, Lei

AU - Diaz-Flores, Ernesto

AU - Walsh, Michael F

AU - Zhang, Jinghui

AU - Ding, Li

AU - Payne-Turner, Debbie

AU - Churchman, Michelle

AU - Andersson, Anna

AU - Chen, Shann-Ching

AU - McCastlain, Kelly

AU - Becksfort, Jared

AU - Ma, Jing

AU - Wu, Gang

AU - Patel, Samir N

AU - Heatley, Susan L

AU - Phillips, Letha A

AU - Song, Guangchun

AU - Easton, John

AU - Parker, Matthew

AU - Chen, Xiang

AU - Rusch, Michael

AU - Boggs, Kristy

AU - Vadodaria, Bhavin

AU - Hedlund, Erin

AU - Drenberg, Christina

AU - Baker, Sharyn D

AU - Pei, Deqing

AU - Cheng, Cheng

AU - Huether, Robert

AU - Lu, Charles

AU - Fulton, Robert S

AU - Fulton, Lucinda L

AU - Tabib, Yashodhan

AU - Dooling, David J

AU - Ochoa, Kerri

AU - Minden, Mark

AU - Lewis, Ian D

AU - To, Luen Bik

AU - Marlton, Paula

AU - Roberts, Andrew W

AU - Raca, Gordana

AU - Stock, Wendy

AU - Neale, Geoffrey

AU - Drexler, Hans G

AU - Dickins, Ross Alexander

AU - Ellison, David W

AU - Shurtleff, Sheila A

AU - Pui, Ching-Hon

AU - Ribeiro, Raul C

AU - Devidas, Meenakshi

AU - Carroll, Andrew J

AU - Heerema, Nyla A

AU - Wood, Brent

AU - Borowitz, Michael J

AU - Gastier-Foster, Julie M

AU - Raimondi, Susana C

AU - Mardis, Elaine R

AU - Wilson, Richard K

AU - Hunger, Stephen P

AU - Downing, James R

AU - Loh, Mignon Lee-Cheun

AU - Mullighan, Charles G

PY - 2013

Y1 - 2013

N2 - The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71 ) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13 ). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2 ) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53 ) and RB1 (41 ). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.

AB - The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71 ) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13 ). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2 ) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53 ) and RB1 (41 ). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.

UR - http://www.nature.com.ezproxy.lib.monash.edu.au/ng/journal/v45/n3/full/ng.2532.html

U2 - 10.1038/ng.2532

DO - 10.1038/ng.2532

M3 - Article

VL - 45

SP - 242

EP - 252

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -

The genomic landscape of hypodiploid acute lymphoblastic leukemia

Abstract

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