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The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

ABSTRACT: Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

SUBMITTER: Andersson AK

PROVIDER: S-EPMC4553269 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Andersson Anna K AK Ma Jing J Wang Jianmin J Chen Xiang X Gedman Amanda Larson AL Dang Jinjun J Nakitandwe Joy J Holmfeldt Linda L Parker Matthew M Easton John J Huether Robert R Kriwacki Richard R Rusch Michael M Wu Gang G Li Yongjin Y Mulder Heather H Raimondi Susana S Pounds Stanley S Kang Guolian G Shi Lei L Becksfort Jared J Gupta Pankaj P Payne-Turner Debbie D Vadodaria Bhavin B Boggs Kristy K Yergeau Donald D Manne Jayanthi J Song Guangchun G Edmonson Michael M Nagahawatte Panduka P Wei Lei L Cheng Cheng C Pei Deqing D Sutton Rosemary R Venn Nicola C NC Chetcuti Albert A Rush Amanda A Catchpoole Daniel D Heldrup Jesper J Fioretos Thoas T Lu Charles C Ding Li L Pui Ching-Hon CH Shurtleff Sheila S Mullighan Charles G CG Mardis Elaine R ER Wilson Richard K RK Gruber Tanja A TA Zhang Jinghui J Downing James R JR

Nature genetics 20150302 4

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of ...[more]

PMID: 25730765

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Project description:Acute lymphoblastic leukemia in infants represents an aggressive malignancy associated with a high incidence (approx. 80%) of translocations involving the Mixed Lineage Leukemia (MLL) gene. Attempts to mimic Mixed Lineage Leukemia fusion driven leukemogenesis in mice raised the question whether these fusion proteins require secondary hits. RAS mutations are suggested as candidates. Earlier results on the incidence of RAS mutations in Mixed Lineage Leukemia-rearranged acute lymphoblastic leukemia are inconclusive. Therefore, we studied frequencies and relation with clinical parameters of RAS mutations in a large cohort of infant acute lymphoblastic leukemia patients. Using conventional sequencing analysis, we screened neuroblastoma RAS viral (v-ras) oncogene homolog gene (NRAS), v-Ki-ras Kirsten rat sarcoma viral oncogene homolog gene (KRAS), and v-raf murine sarcoma viral oncogene homolog B1 gene (BRAF) for mutations in a large cohort (n=109) of infant acute lymphoblastic leukemia patients and studied the mutations in relation to several clinical parameters, and in relation to Homeobox gene A9 expression and the presence of ALL1 fused gene 4-Mixed Lineage Leukemia (AF4-MLL). Mutations were detected in approximately 14% of all cases, with a higher frequency of approximately 24% in t(4;11)-positive patients (P=0.04). Furthermore, we identified RAS mutations as an independent predictor (P=0.019) for poor outcome in Mixed Lineage Leukemia-rearranged infant acute lymphoblastic leukemia, with a hazard ratio of 3.194 (95% confidence interval (CI):1.211-8.429). Also, RAS-mutated infants have higher white blood cell counts at diagnosis (P=0.013), and are more resistant to glucocorticoids in vitro (P<0.05). Finally, we demonstrate that RAS mutations, and not the lack of Homeobox gene A9 expression nor the expression of AF4-MLL are associated with poor outcome in t(4;11)-rearranged infants. We conclude that the presence of RAS mutations in Mixed Lineage Leukemia-rearranged infant acute lymphoblastic leukemia is an independent predictor for a poor outcome. Therefore, future risk-stratification based on abnormal RAS-pathway activation and RAS-pathway inhibition could be beneficial in RAS-mutated infant acute lymphoblastic leukemia patients.

Dataset Information

The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Publications

The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

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