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.

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Figure 1: Genes that distinguish ALL from MLL.
Figure 2: Selected early lymphocyte gene expression in ALL and MLL.
Figure 3: Selected HOX gene expression in ALL and MLL.
Figure 4: Comparison of gene expression between ALL, MLL and AML.
Figure 5: Genes that are specifically expressed in MLL, ALL or AML.
Figure 6: Classification of ALL, MLL and AML on the basis of their gene expression profile.

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Acknowledgements

We thank V. Dalton, S. Waters, A. Cardoso and N. Haining for help with accumulating samples and obtaining clinical data; J. Korsmeyer and D. Neuberg for help with statistical analysis; J. Fletcher for help with interpretation of 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.).

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Correspondence to Todd R. Golub or Stanley J. Korsmeyer.

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Armstrong, S., Staunton, J., Silverman, L. et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 30, 41–47 (2002). https://doi.org/10.1038/ng765

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