PCGP Ph-like ALL

Background: BCR-ABL1-like, or Ph-like acute lymphoblastic leukemia is characterized by a gene expression profile similar to BCR-ABL1 positive ALL, genetic alterations of lymphoid transcription factor genes, and poor outcome. Sequencing of small numbers of Ph-like ALL cases has identified genetic alterations activating kinase signaling suggesting Ph-like ALL may be amenable to treatment with tyrosine kinase inhibitors. However, the spectrum of genetic alterations in childhood and adult Ph-like ALL is incompletely understood. Methods: We performed genomic profiling of 1736 B-ALL cases and next-generation sequencing for 160 Ph-like cases. We examined the functional effects of chimeric fusion proteins in mouse cell lines. Results: The frequency of Ph-like ALL rose from 11% in children to 26% in young adults, and was associated with very poor outcome. Kinase-activating alterations were identified in 90% of Ph-like cases, most commonly fusions involving 10 kinase or cytokine receptor genes (ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B and TYK2), and mutations involving FLT3, IL7R and SH2B3. Expression of ABL1, ABL2, CSF1R and JAK2 fusions resulted in cytokine-independent proliferation of cell lines and activation of pSTAT5. Cells expressing ABL1, ABL2, CSF1R and PDGFRB fusions were sensitive to dasatinib, and JAK2 fusions to ruxolitinib. Conclusions: Ph-like ALL is characterized by a diverse range of genomic alterations that converge on a limited number of kinase signaling pathways amenable to inhibition with currently available tyrosine kinase inhibitors. Trials identifying Ph-like ALL and testing the efficacy of tyrosine kinase inhibitor therapy are warranted

Type: Other
Archiver: EGA European Genome-Phenome Archive

6 Datasets 21 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001000976	WGS DATA FILES FOR SJPhLike	Illumina HiSeq 2000	80
EGAD00001001016	DATA FILES FOR SJPhLike-RNASeq	Illumina HiSeq 2000	125
EGAD00001001054	DATA FILES FOR Ph-likeALL WES	Illumina HiSeq 2000	23
EGAD00001001432	PCGP Germline Study Whole Genome Sequencing	Illumina HiSeq 2000	1337
EGAD00010000596	PCGP Ph-likeALL GEA		837
EGAD00010000598	PCGP Ph-likeALL SNP6		1724

Publications	Citations
Outcomes of children with BCR-ABL1–like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease. Roberts KG, Pei D, Campana D, Payne-Turner D, Li Y, Cheng C, Sandlund JT, Jeha S, Easton J, Becksfort J, Zhang J, Coustan-Smith E, Raimondi SC, Leung WH, Relling MV, Evans WE, Downing JR, Mullighan CG, Pui CH. J Clin Oncol 32: 2014 3012-3020	133
Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D, McCastlain K, Ding L, Lu C, Song G, Ma J, Becksfort J, Rusch M, Chen SC, Easton J, Cheng J, Boggs K, Santiago-Morales N, Iacobucci I, Fulton RS, Wen J, Valentine M, Cheng C, Paugh SW, Devidas M, Chen IM, Reshmi S, Smith A, Hedlund E, Gupta P, Nagahawatte P, Wu G, Chen X, Yergeau D, Vadodaria B, Mulder H, Winick NJ, Larsen EC, Carroll WL, Heerema NA, Carroll AJ, Grayson G, Tasian SK, Moore AS, Keller F, Frei-Jones M, Whitlock JA, Raetz EA, White DL, Hughes TP, Guidry Auvil JM, Smith MA, Marcucci G, Bloomfield CD, Mrózek K, Kohlschmidt J, Stock W, Kornblau SM, Konopleva M, Paietta E, Pui CH, Jeha S, Relling MV, Evans WE, Gerhard DS, Gastier-Foster JM, Mardis E, Wilson RK, Loh ML, Downing JR, Hunger SP, Willman CL, Zhang J, Mullighan CG. N Engl J Med 371: 2014 1005-1015	686
Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. Topka S, Vijai J, Walsh MF, Jacobs L, Maria A, Villano D, Gaddam P, Wu G, McGee RB, Quinn E, Inaba H, Hartford C, Pui CH, Pappo A, Edmonson M, Zhang MY, Stepensky P, Steinherz P, Schrader K, Lincoln A, Bussel J, Lipkin SM, Goldgur Y, Harit M, Stadler ZK, Mullighan C, Weintraub M, Shimamura A, Zhang J, Downing JR, Nichols KE, Offit K. PLoS Genet 11: 2015 e1005262	67
Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children. Xu H, Zhang H, Yang W, Yadav R, Morrison AC, Qian M, Devidas M, Liu Y, Perez-Andreu V, Zhao X, Gastier-Foster JM, Lupo PJ, Neale G, Raetz E, Larsen E, Bowman WP, Carroll WL, Winick N, Williams R, Hansen T, Holm JC, Mardis E, Fulton R, Pui CH, Zhang J, Mullighan CG, Evans WE, Hunger SP, Gupta R, Schmiegelow K, Loh ML, Relling MV, Yang JJ. Nat Commun 6: 2015 7553	48
Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia. Iacobucci I, Li Y, Roberts KG, Dobson SM, Kim JC, Payne-Turner D, Harvey RC, Valentine M, McCastlain K, Easton J, Yergeau D, Janke LJ, Shao Y, Chen IM, Rusch M, Zandi S, Kornblau SM, Konopleva M, Jabbour E, Paietta EM, Rowe JM, Pui CH, Gastier-Foster J, Gu Z, Reshmi S, Loh ML, Racevskis J, Tallman MS, Wiernik PH, Litzow MR, Willman CL, McPherson JD, Downing JR, Zhang J, Dick JE, Hunger SP, Mullighan CG. Cancer Cell 29: 2016 186-200	72
Deregulation of DUX4 and ERG in acute lymphoblastic leukemia. Zhang J, McCastlain K, Yoshihara H, Xu B, Chang Y, Churchman ML, Wu G, Li Y, Wei L, Iacobucci I, Liu Y, Qu C, Wen J, Edmonson M, Payne-Turner D, Kaufmann KB, Takayanagi SI, Wienholds E, Waanders E, Ntziachristos P, Bakogianni S, Wang J, Aifantis I, Roberts KG, Ma J, Song G, Easton J, Mulder HL, Chen X, Newman S, Ma X, Rusch M, Gupta P, Boggs K, Vadodaria B, Dalton J, Liu Y, Valentine ML, Ding L, Lu C, Fulton RS, Fulton L, Tabib Y, Ochoa K, Devidas M, Pei D, Cheng C, Yang J, Evans WE, Relling MV, Pui CH, Jeha S, Harvey RC, Chen IL, Willman CL, Marcucci G, Bloomfield CD, Kohlschmidt J, Mrózek K, Paietta E, Tallman MS, Stock W, Foster MC, Racevskis J, Rowe JM, Luger S, Kornblau SM, Shurtleff SA, Raimondi SC, Mardis ER, Wilson RK, Dick JE, Hunger SP, Loh ML, Downing JR, Mullighan CG, St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. Nat Genet 48: 2016 1481-1489	141
Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia. Gu Z, Churchman M, Roberts K, Li Y, Liu Y, Harvey RC, McCastlain K, Reshmi SC, Payne-Turner D, Iacobucci I, Shao Y, Chen IM, Valentine M, Pei D, Mungall KL, Mungall AJ, Ma Y, Moore R, Marra M, Stonerock E, Gastier-Foster JM, Devidas M, Dai Y, Wood B, Borowitz M, Larsen EE, Maloney K, Mattano LA, Angiolillo A, Salzer WL, Burke MJ, Gianni F, Spinelli O, Radich JP, Minden MD, Moorman AV, Patel B, Fielding AK, Rowe JM, Luger SM, Bhatia R, Aldoss I, Forman SJ, Kohlschmidt J, Mrózek K, Marcucci G, Bloomfield CD, Stock W, Kornblau S, Kantarjian HM, Konopleva M, Paietta E, Willman CL, Loh ML, Hunger SP, Mullighan CG. Nat Commun 7: 2016 13331	127
High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults. Roberts KG, Gu Z, Payne-Turner D, McCastlain K, Harvey RC, Chen IM, Pei D, Iacobucci I, Valentine M, Pounds SB, Shi L, Li Y, Zhang J, Cheng C, Rambaldi A, Tosi M, Spinelli O, Radich JP, Minden MD, Rowe JM, Luger S, Litzow MR, Tallman MS, Wiernik PH, Bhatia R, Aldoss I, Kohlschmidt J, Mrózek K, Marcucci G, Bloomfield CD, Stock W, Kornblau S, Kantarjian HM, Konopleva M, Paietta E, Willman CL, Mullighan CG. J Clin Oncol 35: 2017 394-401	153
Leukaemic alterations of IKZF1 prime stemness and malignancy programs in human lymphocytes. Li Z, Li SP, Li RY, Zhu H, Liu X, Guo XL, Mu LL, Cai JJ, Bai F, Chen GQ, Hong DL. Cell Death Dis 9: 2018 526	3
Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. Li JF, Dai YT, Lilljebjörn H, Shen SH, Cui BW, Bai L, Liu YF, Qian MX, Kubota Y, Kiyoi H, Matsumura I, Miyazaki Y, Olsson L, Tan AM, Ariffin H, Chen J, Takita J, Yasuda T, Mano H, Johansson B, Yang JJ, Yeoh AE, Hayakawa F, Chen Z, Pui CH, Fioretos T, Chen SJ, Huang JY. Proc Natl Acad Sci U S A 115: 2018 E11711-E11720	108
PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Gu Z, Churchman ML, Roberts KG, Moore I, Zhou X, Nakitandwe J, Hagiwara K, Pelletier S, Gingras S, Berns H, Payne-Turner D, Hill A, Iacobucci I, Shi L, Pounds S, Cheng C, Pei D, Qu C, Newman S, Devidas M, Dai Y, Reshmi SC, Gastier-Foster J, Raetz EA, Borowitz MJ, Wood BL, Carroll WL, Zweidler-McKay PA, Rabin KR, Mattano LA, Maloney KW, Rambaldi A, Spinelli O, Radich JP, Minden MD, Rowe JM, Luger S, Litzow MR, Tallman MS, Racevskis J, Zhang Y, Bhatia R, Kohlschmidt J, Mrózek K, Bloomfield CD, Stock W, Kornblau S, Kantarjian HM, Konopleva M, Evans WE, Jeha S, Pui CH, Yang J, Paietta E, Downing JR, Relling MV, Zhang J, Loh ML, Hunger SP, Mullighan CG. Nat Genet 51: 2019 296-307	206
Long-read sequencing unveils IGH-DUX4 translocation into the silenced IGH allele in B-cell acute lymphoblastic leukemia. Tian L, Shao Y, Nance S, Dang J, Xu B, Ma X, Li Y, Ju B, Dong L, Newman S, Zhou X, Schreiner P, Tseng E, Hon T, Ashby M, Li C, Easton J, Gruber TA, Zhang J. Nat Commun 10: 2019 2789	8
CICERO: a versatile method for detecting complex and diverse driver fusions using cancer RNA sequencing data. Tian L, Li Y, Edmonson MN, Zhou X, Newman S, McLeod C, Thrasher A, Liu Y, Tang B, Rusch MC, Easton J, Ma J, Davis E, Trull A, Michael JR, Szlachta K, Mullighan C, Baker SJ, Downing JR, Ellison DW, Zhang J. Genome Biol 21: 2020 126	36
Functional interrogation of HOXA9 regulome in MLLr leukemia via reporter-based CRISPR/Cas9 screen. Zhang H, Zhang Y, Zhou X, Wright S, Hyle J, Zhao L, An J, Zhao X, Shao Y, Xu B, Lee HM, Chen T, Zhou Y, Chen X, Lu R, Li C. Elife 9: 2020 e57858	16
Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL. Paietta E, Roberts KG, Wang V, Gu Z, Buck GAN, Pei D, Cheng C, Levine RL, Abdel-Wahab O, Cheng Z, Wu G, Qu C, Shi L, Pounds S, Willman CL, Harvey R, Racevskis J, Barinka J, Zhang Y, Dewald GW, Ketterling RP, Alejos D, Lazarus HM, Luger SM, Foroni L, Patel B, Fielding AK, Melnick A, Marks DI, Moorman AV, Wiernik PH, Rowe JM, Tallman MS, Goldstone AH, Mullighan CG, Litzow MR. Blood 138: 2021 948-958	29
Clinical significance of novel subtypes of acute lymphoblastic leukemia in the context of minimal residual disease-directed therapy. Jeha S, Choi J, Roberts KG, Pei D, Coustan-Smith E, Inaba H, Rubnitz JE, Ribeiro RC, Gruber TA, Raimondi SC, Karol SE, Qu C, Brady SW, Gu Z, Yang JJ, Cheng C, Downing JR, Evans WE, Relling MV, Campana D, Mullighan CG, Pui CH. Blood Cancer Discov 2: 2021 326-337	33
Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia. Kimura S, Montefiori L, Iacobucci I, Zhao Y, Gao Q, Paietta EM, Haferlach C, Laird AD, Mead PE, Gu Z, Stock W, Litzow M, Rowe JM, Luger SM, Hunger SP, Ryland GL, Schmidt B, Ekert PG, Oshlack A, Grimmond SM, Rehn J, Breen J, Yeung D, White DL, Aldoss I, Jabbour EJ, Pui CH, Meggendorfer M, Walter W, Kern W, Haferlach T, Brady S, Zhang J, Roberts KG, Blombery P, Mullighan CG. Blood 139: 2022 3519-3531	9
Functional, structural, and molecular characterizations of the leukemogenic driver MEF2D-HNRNPUL1 fusion. Zhang M, Zhang H, Li Z, Bai L, Wang Q, Li J, Jiang M, Xue Q, Cheng N, Zhang W, Mao D, Chen Z, Huang J, Meng G, Chen Z, Chen SJ. Blood 140: 2022 1390-1407	2
Acute lymphoblastic leukemia displays a distinct highly methylated genome. Hetzel S, Mattei AL, Kretzmer H, Qu C, Chen X, Fan Y, Wu G, Roberts KG, Luger S, Litzow M, Rowe J, Paietta E, Stock W, Mardis ER, Wilson RK, Downing JR, Mullighan CG, Meissner A. Nat Cancer 3: 2022 768-782	6
The genomic landscape of pediatric acute lymphoblastic leukemia. Brady SW, Roberts KG, Gu Z, Shi L, Pounds S, Pei D, Cheng C, Dai Y, Devidas M, Qu C, Hill AN, Payne-Turner D, Ma X, Iacobucci I, Baviskar P, Wei L, Arunachalam S, Hagiwara K, Liu Y, Flasch DA, Liu Y, Parker M, Chen X, Elsayed AH, Pathak O, Li Y, Fan Y, Michael JR, Rusch M, Wilkinson MR, Foy S, Hedges DJ, Newman S, Zhou X, Wang J, Reilly C, Sioson E, Rice SV, Pastor Loyola V, Wu G, Rampersaud E, Reshmi SC, Gastier-Foster J, Guidry Auvil JM, Gesuwan P, Smith MA, Winick N, Carroll AJ, Heerema NA, Harvey RC, Willman CL, Larsen E, Raetz EA, Borowitz MJ, Wood BL, Carroll WL, Zweidler-McKay PA, Rabin KR, Mattano LA, Maloney KW, Winter SS, Burke MJ, Salzer W, Dunsmore KP, Angiolillo AL, Crews KR, Downing JR, Jeha S, Pui CH, Evans WE, Yang JJ, Relling MV, Gerhard DS, Loh ML, Hunger SP, Zhang J, Mullighan CG. Nat Genet 54: 2022 1376-1389	28
Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response. Lee SHR, Yang W, Gocho Y, John A, Rowland L, Smart B, Williams H, Maxwell D, Hunt J, Yang W, Crews KR, Roberts KG, Jeha S, Cheng C, Karol SE, Relling MV, Rosner GL, Inaba H, Mullighan CG, Pui CH, Evans WE, Yang JJ. Nat Med 29: 2023 170-179	4