[Show abstract][Hide abstract] ABSTRACT: Treatment of pediatric acute lymphoblastic leukemia (ALL) is based on the concept of tailoring the intensity of therapy to a patient's risk of relapse. To determine whether gene expression profiling could enhance risk assignment, we used oligonucleotide microarrays to analyze the pattern of genes expressed in leukemic blasts from 360 pediatric ALL patients. Distinct expression profiles identified each of the prognostically important leukemia subtypes, including T-ALL, E2A-PBX1, BCR-ABL, TEL-AML1, MLL rearrangement, and hyperdiploid >50 chromosomes. In addition, another ALL subgroup was identified based on its unique expression profile. Examination of the genes comprising the expression signatures provided important insights into the biology of these leukemia subgroups. Further, within some genetic subgroups, expression profiles identified those patients that would eventually fail therapy. Thus, the single platform of expression profiling should enhance the accurate risk stratification of pediatric ALL patients.
[Show abstract][Hide abstract] ABSTRACT: The AML1/CBFbeta transcription factor complex, a frequent target of chromosomal translocations in leukemia, is essential for the generation of definitive hematopoietic stem cells. Paradoxically, expression of the acute myeloid leukemia-associated AML1-ETO fusion protein in mice results not in leukemia, but in embryonic lethality due to an absence of normal hematopoiesis. To bypass the embryonic lethality, we generated a mouse strain with a conditional AML1-ETO knockin allele that contains a loxP bracketed transcriptional stop cassette 5' to the AML1-ETO fusion site. Activation of this allele in vivo by Cre-mediated recombination resulted in an enhanced replating efficiency of myeloid progenitors, but it did not block their differentiation, nor was it sufficient to induce leukemia. However, induction of cooperating mutations resulted in the development of an acute myeloid disease that mimicked many of the features of human AML1-ETO-expressing leukemia.