MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia

Scott A Armstrong; Jane E Staunton; Lewis B Silverman; Rob Pieters; Monique L den Boer; Mark D Minden; Stephen E Sallan; Eric S Lander; Todd R Golub; Stanley J Korsmeyer

doi:10.1038/ng765

MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia

Scott A Armstrong
, Jane E Staunton
, Lewis B Silverman
, Rob Pieters
, Monique L den Boer
, Mark D Minden
, Stephen E Sallan
, Eric S Lander
, Todd R Golub
, Stanley J Korsmeyer

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

1740 Citations (Scopus)

Abstract

Acute lymphoblastic leukemias carrying a chromosomal translocation involving the mixed-lineage leukemia gene (MLL, ALL1, HRX) have a particularly poor prognosis. Here we show that they have a characteristic, highly distinct gene expression profile that is consistent with an early hematopoietic progenitor expressing select multilineage markers and individual HOX genes. Clustering algorithms reveal that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. We propose that they constitute a distinct disease, denoted here as MLL, and show that the differences in gene expression are robust enough to classify leukemias correctly as MLL, acute lymphoblastic leukemia or acute myelogenous leukemia. Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets.

Original language	English
Pages (from-to)	41-7
Number of pages	7
Journal	Nature genetics
Volume	30
Issue number	1
DOIs	https://doi.org/10.1038/ng765
Publication status	Published - Jan 2002
Externally published	Yes

Keywords

Acute Disease
Cell Lineage
DNA-Binding Proteins/genetics
Gene Expression Profiling
Gene Expression Regulation, Leukemic/genetics
Genes, Homeobox
Hematopoietic Stem Cells/metabolism
Histone-Lysine N-Methyltransferase
Homeodomain Proteins/biosynthesis
Humans
Immunophenotyping
Leukemia, Myeloid/classification
Myeloid-Lymphoid Leukemia Protein
Neoplasm Proteins/biosynthesis
Neoplastic Stem Cells/metabolism
Oligonucleotide Array Sequence Analysis
Oncogene Proteins, Fusion/biosynthesis
Precursor Cell Lymphoblastic Leukemia-Lymphoma/classification
Proto-Oncogenes
RNA, Messenger/biosynthesis
RNA, Neoplasm/biosynthesis
Transcription Factors
Translocation, Genetic

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10.1038/ng765

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title = "MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia",

abstract = "Acute lymphoblastic leukemias carrying a chromosomal translocation involving the mixed-lineage leukemia gene (MLL, ALL1, HRX) have a particularly poor prognosis. Here we show that they have a characteristic, highly distinct gene expression profile that is consistent with an early hematopoietic progenitor expressing select multilineage markers and individual HOX genes. Clustering algorithms reveal that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. We propose that they constitute a distinct disease, denoted here as MLL, and show that the differences in gene expression are robust enough to classify leukemias correctly as MLL, acute lymphoblastic leukemia or acute myelogenous leukemia. Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets.",

keywords = "Acute Disease, Cell Lineage, DNA-Binding Proteins/genetics, Gene Expression Profiling, Gene Expression Regulation, Leukemic/genetics, Genes, Homeobox, Hematopoietic Stem Cells/metabolism, Histone-Lysine N-Methyltransferase, Homeodomain Proteins/biosynthesis, Humans, Immunophenotyping, Leukemia, Myeloid/classification, Myeloid-Lymphoid Leukemia Protein, Neoplasm Proteins/biosynthesis, Neoplastic Stem Cells/metabolism, Oligonucleotide Array Sequence Analysis, Oncogene Proteins, Fusion/biosynthesis, Precursor Cell Lymphoblastic Leukemia-Lymphoma/classification, Proto-Oncogenes, RNA, Messenger/biosynthesis, RNA, Neoplasm/biosynthesis, Transcription Factors, Translocation, Genetic",

author = "Armstrong, \{Scott A\} and Staunton, \{Jane E\} and Silverman, \{Lewis B\} and Rob Pieters and \{den Boer\}, \{Monique L\} and Minden, \{Mark D\} and Sallan, \{Stephen E\} and Lander, \{Eric S\} and Golub, \{Todd R\} and Korsmeyer, \{Stanley J\}",

note = "Funding Information: cytogenetic data; E. Smith for assistance with figures and editing; C. Ladd, M. Angelo and other members of the Whitehead/MIT Center for Genome Research Program in Cancer Genomics for technical help and developing data analysis tools and P. Ernst and J. Hsieh for discussions. This work was supported in part by an NIH grant, an American Society of Hematology Fellow Scholar Award (S.A.A.), an American Society of Hematology Junior Faculty Scholar Award (T.R.G.), the Belfer Cancer Genomics Center and Bristol-Myers Squibb, Millennium Pharmaceuticals, and Affymetrix (T.R.G.).",

year = "2002",

month = jan,

doi = "10.1038/ng765",

language = "English",

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T1 - MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia

AU - Armstrong, Scott A

AU - Staunton, Jane E

AU - Silverman, Lewis B

AU - Pieters, Rob

AU - den Boer, Monique L

AU - Minden, Mark D

AU - Sallan, Stephen E

AU - Lander, Eric S

AU - Golub, Todd R

AU - Korsmeyer, Stanley J

N1 - Funding Information: cytogenetic data; E. Smith for assistance with figures and editing; C. Ladd, M. Angelo and other members of the Whitehead/MIT Center for Genome Research Program in Cancer Genomics for technical help and developing data analysis tools and P. Ernst and J. Hsieh for discussions. This work was supported in part by an NIH grant, an American Society of Hematology Fellow Scholar Award (S.A.A.), an American Society of Hematology Junior Faculty Scholar Award (T.R.G.), the Belfer Cancer Genomics Center and Bristol-Myers Squibb, Millennium Pharmaceuticals, and Affymetrix (T.R.G.).

PY - 2002/1

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N2 - Acute lymphoblastic leukemias carrying a chromosomal translocation involving the mixed-lineage leukemia gene (MLL, ALL1, HRX) have a particularly poor prognosis. Here we show that they have a characteristic, highly distinct gene expression profile that is consistent with an early hematopoietic progenitor expressing select multilineage markers and individual HOX genes. Clustering algorithms reveal that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. We propose that they constitute a distinct disease, denoted here as MLL, and show that the differences in gene expression are robust enough to classify leukemias correctly as MLL, acute lymphoblastic leukemia or acute myelogenous leukemia. Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets.

AB - Acute lymphoblastic leukemias carrying a chromosomal translocation involving the mixed-lineage leukemia gene (MLL, ALL1, HRX) have a particularly poor prognosis. Here we show that they have a characteristic, highly distinct gene expression profile that is consistent with an early hematopoietic progenitor expressing select multilineage markers and individual HOX genes. Clustering algorithms reveal that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. We propose that they constitute a distinct disease, denoted here as MLL, and show that the differences in gene expression are robust enough to classify leukemias correctly as MLL, acute lymphoblastic leukemia or acute myelogenous leukemia. Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets.

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KW - Cell Lineage

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KW - Gene Expression Regulation, Leukemic/genetics

KW - Genes, Homeobox

KW - Hematopoietic Stem Cells/metabolism

KW - Histone-Lysine N-Methyltransferase

KW - Homeodomain Proteins/biosynthesis

KW - Humans

KW - Immunophenotyping

KW - Leukemia, Myeloid/classification

KW - Myeloid-Lymphoid Leukemia Protein

KW - Neoplasm Proteins/biosynthesis

KW - Neoplastic Stem Cells/metabolism

KW - Oligonucleotide Array Sequence Analysis

KW - Oncogene Proteins, Fusion/biosynthesis

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/classification

KW - Proto-Oncogenes

KW - RNA, Messenger/biosynthesis

KW - RNA, Neoplasm/biosynthesis

KW - Transcription Factors

KW - Translocation, Genetic

UR - https://www.scopus.com/pages/publications/18544375333

U2 - 10.1038/ng765

DO - 10.1038/ng765

M3 - Article

C2 - 11731795

SN - 1061-4036

VL - 30

SP - 41

EP - 47

JO - Nature genetics

JF - Nature genetics

IS - 1

ER -

MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia

Abstract

Keywords

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