Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia

Ina Radtke, Charles G. Mullighan, Masami Ishii, Xiaoping Su, Jinjun Cheng, Jing Ma, Ramapriya Ganti, Zhongling Cai, Salil Goorha, Stanley B. Pounds, Xueyuan Cao, Caroline Obert, Jianling Armstrong, Jinghui Zhang, Guangchun Song, Raul C. Ribeiro, Jeffrey E. Rubnitz, Susana C. Raimondi, Sheila A. Shurtleff, James R. Downing

Research output: Contribution to journalArticle

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Abstract

Pediatric de novo acute myeloid leukemia (AML) is an aggressive malignancy with current therapy resulting in cure rates of only 60%. To better understand the cause of the marked heterogeneity in therapeutic response and to identify new prognostic markers and therapeutic targets a comprehensive list of the genetic mutations that underlie the pathogenesis of AML is needed. To approach this goal, we examined diagnostic leukemic samples from a cohort of 111 children with de novo AML using single-nucleotide-polymorphism microarrays and candidate gene resequencing. Our data demonstrate that, in contrast to pediatric acute lymphoblastic leukemia (ALL), de novo AML is characterized by a very low burden of genomic alterations, with a mean of only 2.38 somatic copy-number alterations per leukemia, and less than 1 nonsynonymous point mutation per leukemia in the 25 genes analyzed. Even more surprising was the observation that 34% of the leukemias lacked any identifiable copy-number alterations, and 28% of the leukemias with recurrent translocations lacked any identifiable sequence or numerical abnormalities. The only exception to the presence of few mutations was acute megakaryocytic leukemias, with the majority of these leukemias being characterized by a high number of copy-number alterations but rare point mutations. Despite the low overall number of lesions across the patient cohort, novel recurring regions of genetic alteration were identified that harbor known, and potential new cancer genes. These data reflect a remarkably low burden of genomic alterations within pediatric de novo AML, which is in stark contrast to most other human malignancies.

Original languageEnglish (US)
Pages (from-to)12944-12949
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number31
DOIs
StatePublished - Aug 4 2009

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Acute Myeloid Leukemia
Leukemia
Pediatrics
Point Mutation
Leukemia, Megakaryoblastic, Acute
Mutation
Neoplasm Genes
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Genes
Single Nucleotide Polymorphism
Neoplasms
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

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Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia. / Radtke, Ina; Mullighan, Charles G.; Ishii, Masami; Su, Xiaoping; Cheng, Jinjun; Ma, Jing; Ganti, Ramapriya; Cai, Zhongling; Goorha, Salil; Pounds, Stanley B.; Cao, Xueyuan; Obert, Caroline; Armstrong, Jianling; Zhang, Jinghui; Song, Guangchun; Ribeiro, Raul C.; Rubnitz, Jeffrey E.; Raimondi, Susana C.; Shurtleff, Sheila A.; Downing, James R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 31, 04.08.2009, p. 12944-12949.

Research output: Contribution to journalArticle

Radtke, I, Mullighan, CG, Ishii, M, Su, X, Cheng, J, Ma, J, Ganti, R, Cai, Z, Goorha, S, Pounds, SB, Cao, X, Obert, C, Armstrong, J, Zhang, J, Song, G, Ribeiro, RC, Rubnitz, JE, Raimondi, SC, Shurtleff, SA & Downing, JR 2009, 'Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 31, pp. 12944-12949. https://doi.org/10.1073/pnas.0903142106
Radtke, Ina ; Mullighan, Charles G. ; Ishii, Masami ; Su, Xiaoping ; Cheng, Jinjun ; Ma, Jing ; Ganti, Ramapriya ; Cai, Zhongling ; Goorha, Salil ; Pounds, Stanley B. ; Cao, Xueyuan ; Obert, Caroline ; Armstrong, Jianling ; Zhang, Jinghui ; Song, Guangchun ; Ribeiro, Raul C. ; Rubnitz, Jeffrey E. ; Raimondi, Susana C. ; Shurtleff, Sheila A. ; Downing, James R. / Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 31. pp. 12944-12949.
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AU - Radtke, Ina

AU - Mullighan, Charles G.

AU - Ishii, Masami

AU - Su, Xiaoping

AU - Cheng, Jinjun

AU - Ma, Jing

AU - Ganti, Ramapriya

AU - Cai, Zhongling

AU - Goorha, Salil

AU - Pounds, Stanley B.

AU - Cao, Xueyuan

AU - Obert, Caroline

AU - Armstrong, Jianling

AU - Zhang, Jinghui

AU - Song, Guangchun

AU - Ribeiro, Raul C.

AU - Rubnitz, Jeffrey E.

AU - Raimondi, Susana C.

AU - Shurtleff, Sheila A.

AU - Downing, James R.

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N2 - Pediatric de novo acute myeloid leukemia (AML) is an aggressive malignancy with current therapy resulting in cure rates of only 60%. To better understand the cause of the marked heterogeneity in therapeutic response and to identify new prognostic markers and therapeutic targets a comprehensive list of the genetic mutations that underlie the pathogenesis of AML is needed. To approach this goal, we examined diagnostic leukemic samples from a cohort of 111 children with de novo AML using single-nucleotide-polymorphism microarrays and candidate gene resequencing. Our data demonstrate that, in contrast to pediatric acute lymphoblastic leukemia (ALL), de novo AML is characterized by a very low burden of genomic alterations, with a mean of only 2.38 somatic copy-number alterations per leukemia, and less than 1 nonsynonymous point mutation per leukemia in the 25 genes analyzed. Even more surprising was the observation that 34% of the leukemias lacked any identifiable copy-number alterations, and 28% of the leukemias with recurrent translocations lacked any identifiable sequence or numerical abnormalities. The only exception to the presence of few mutations was acute megakaryocytic leukemias, with the majority of these leukemias being characterized by a high number of copy-number alterations but rare point mutations. Despite the low overall number of lesions across the patient cohort, novel recurring regions of genetic alteration were identified that harbor known, and potential new cancer genes. These data reflect a remarkably low burden of genomic alterations within pediatric de novo AML, which is in stark contrast to most other human malignancies.

AB - Pediatric de novo acute myeloid leukemia (AML) is an aggressive malignancy with current therapy resulting in cure rates of only 60%. To better understand the cause of the marked heterogeneity in therapeutic response and to identify new prognostic markers and therapeutic targets a comprehensive list of the genetic mutations that underlie the pathogenesis of AML is needed. To approach this goal, we examined diagnostic leukemic samples from a cohort of 111 children with de novo AML using single-nucleotide-polymorphism microarrays and candidate gene resequencing. Our data demonstrate that, in contrast to pediatric acute lymphoblastic leukemia (ALL), de novo AML is characterized by a very low burden of genomic alterations, with a mean of only 2.38 somatic copy-number alterations per leukemia, and less than 1 nonsynonymous point mutation per leukemia in the 25 genes analyzed. Even more surprising was the observation that 34% of the leukemias lacked any identifiable copy-number alterations, and 28% of the leukemias with recurrent translocations lacked any identifiable sequence or numerical abnormalities. The only exception to the presence of few mutations was acute megakaryocytic leukemias, with the majority of these leukemias being characterized by a high number of copy-number alterations but rare point mutations. Despite the low overall number of lesions across the patient cohort, novel recurring regions of genetic alteration were identified that harbor known, and potential new cancer genes. These data reflect a remarkably low burden of genomic alterations within pediatric de novo AML, which is in stark contrast to most other human malignancies.

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