The genomic landscape of hypodiploid acute lymphoblastic leukemia

Linda Holmfeldt; Lei Wei; Ernesto Diaz-Flores; Michael 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 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; L. Bik To; Paula Marlton; Andrew W. Roberts; Gordana Raca; Wendy Stock; Geoffrey Neale; Hans G. Drexler; Ross A. 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; James R. Downing; Stephen P. Hunger; Mignon L. 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 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 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, L. Bik To, Paula Marlton, Andrew W. Roberts, Gordana Raca, Wendy Stock, Geoffrey Neale, Hans G. Drexler, Ross A. 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, James R. Downing, Stephen P. Hunger, Mignon L. Loh, Charles G. Mullighan

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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
Issue number	3
DOIs	https://doi.org/10.1038/ng.2532
State	Published - Mar 2013

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Holmfeldt, L., Wei, L., Diaz-Flores, E., Walsh, M., 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(3), 242-252. https://doi.org/10.1038/ng.2532

@article{f6eff1dc73cd422194e62da6fb17b47b,

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 Michael Walsh and Jinghui Zhang and Li Ding and Debbie Payne-Turner and Michelle Churchman and Anna Andersson and Chen, {Shann Ching} 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 Sharyn Baker 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, {L. Bik} and Paula Marlton and Roberts, {Andrew W.} and Gordana Raca and Wendy Stock and Geoffrey Neale and Drexler, {Hans G.} and Dickins, {Ross A.} and Ellison, {David W.} and Shurtleff, {Sheila A.} and Pui, {Ching Hon} 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 Downing, {James R.} and Hunger, {Stephen P.} and Loh, {Mignon L.} and Mullighan, {Charles G.}",

note = "Funding Information: We thank J. Morris, E. Walker and A. Merriman for performing SNP and gene expression microarrays and G. Zambetti and P. Brindle for insightful discussions of TP53 and CREBBP mutational data, respectively. We also thank H. Mulder, R. Collins, M. Barbato, E. Stonerock, E. Pinto and M. Ellis for technical assistance, the Tissue Resources Core facility and the Flow Cytometry and Cell Sorting Core facility of the St. Jude Children{\textquoteright}s Research Hospital (SJCRH). This work was supported by The Henry Schueler 41&9 Foundation in conjunction with Partnership for Cures, the St. Baldrick{\textquoteright}s Foundation, US National Cancer Institute (NCI) grant RC4CA156329, US National Institutes of Health (NIH) grants CA21765 and U01 GM92666, the American Association for Cancer Research (AACR) Gertrude B. Elion Cancer Research Award and the American Lebanese and Syrian Associated Charities (ALSAC) of SJCRH. Support was also provided by NCI grants to the Children{\textquoteright}s Oncology Group, including CA98543, CA98413 and CA114766. L.H. was supported by the Swedish Research Council. S.P.H. is the Ergen Family Chair in Pediatric Cancer. M.L.L. is a Clinical Scholar in the Leukemia Lymphoma Society and supported by the Frank A. Campini Foundation. C.G.M. is a Pew Scholar in the Biomedical Sciences and a St. Baldrick{\textquoteright}s Scholar. M.L.L. and E.D.-F. were supported by the Team Connor Foundation, and S.N.P. was supported by 5R25CA023944 from NCI. This paper is dedicated to Henry {\textquoteleft}Hank{\textquoteright} Schueler who died from complications of hypodiploid ALL and whose Foundation is dedicated to finding a cure for hypodiploid ALL in his memory and to James B. Nachman who was instrumental in the genesis of this project and who recently passed away.",

year = "2013",

month = mar,

doi = "10.1038/ng.2532",

language = "English",

volume = "45",

pages = "242--252",

journal = "Nature Genetics",

issn = "1061-4036",

number = "3",

}

Holmfeldt, L, Wei, L, Diaz-Flores, E, Walsh, M, Zhang, J, Ding, L, Payne-Turner, D, Churchman, M, Andersson, A, Chen, SC, 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, S, 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, CH, Ribeiro, RC, Devidas, M, Carroll, AJ, Heerema, NA, Wood, B, Borowitz, MJ, Gastier-Foster, JM, Raimondi, SC, Mardis, ER, Wilson, RK, Downing, JR, Hunger, SP, Loh, ML & Mullighan, CG 2013, 'The genomic landscape of hypodiploid acute lymphoblastic leukemia', Nature Genetics, vol. 45, no. 3, pp. 242-252. https://doi.org/10.1038/ng.2532

TY - JOUR

T1 - The genomic landscape of hypodiploid acute lymphoblastic leukemia

AU - Holmfeldt, Linda

AU - Wei, Lei

AU - Diaz-Flores, Ernesto

AU - Walsh, Michael

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

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, L. Bik

AU - Marlton, Paula

AU - Roberts, Andrew W.

AU - Raca, Gordana

AU - Stock, Wendy

AU - Neale, Geoffrey

AU - Drexler, Hans G.

AU - Dickins, Ross A.

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 - Downing, James R.

AU - Hunger, Stephen P.

AU - Loh, Mignon L.

AU - Mullighan, Charles G.

N1 - Funding Information: We thank J. Morris, E. Walker and A. Merriman for performing SNP and gene expression microarrays and G. Zambetti and P. Brindle for insightful discussions of TP53 and CREBBP mutational data, respectively. We also thank H. Mulder, R. Collins, M. Barbato, E. Stonerock, E. Pinto and M. Ellis for technical assistance, the Tissue Resources Core facility and the Flow Cytometry and Cell Sorting Core facility of the St. Jude Children’s Research Hospital (SJCRH). This work was supported by The Henry Schueler 41&9 Foundation in conjunction with Partnership for Cures, the St. Baldrick’s Foundation, US National Cancer Institute (NCI) grant RC4CA156329, US National Institutes of Health (NIH) grants CA21765 and U01 GM92666, the American Association for Cancer Research (AACR) Gertrude B. Elion Cancer Research Award and the American Lebanese and Syrian Associated Charities (ALSAC) of SJCRH. Support was also provided by NCI grants to the Children’s Oncology Group, including CA98543, CA98413 and CA114766. L.H. was supported by the Swedish Research Council. S.P.H. is the Ergen Family Chair in Pediatric Cancer. M.L.L. is a Clinical Scholar in the Leukemia Lymphoma Society and supported by the Frank A. Campini Foundation. C.G.M. is a Pew Scholar in the Biomedical Sciences and a St. Baldrick’s Scholar. M.L.L. and E.D.-F. were supported by the Team Connor Foundation, and S.N.P. was supported by 5R25CA023944 from NCI. This paper is dedicated to Henry ‘Hank’ Schueler who died from complications of hypodiploid ALL and whose Foundation is dedicated to finding a cure for hypodiploid ALL in his memory and to James B. Nachman who was instrumental in the genesis of this project and who recently passed away.

PY - 2013/3

Y1 - 2013/3

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.scopus.com/inward/record.url?scp=84874647204&partnerID=8YFLogxK

U2 - 10.1038/ng.2532

DO - 10.1038/ng.2532

M3 - Article

C2 - 23334668

AN - SCOPUS:84874647204

SN - 1061-4036

VL - 45

SP - 242

EP - 252

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

The genomic landscape of hypodiploid acute lymphoblastic leukemia

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