Expression profiles of acute lymphoblastic and myeloblastic leukemias with ALL-1 rearrangements

Abstract

The ALL-1 gene is directly involved in 5-10% of acute lymphoblastic leukemias (ALLs) and acute myeloid leukemias (AMLs) by fusion to other genes or through internal rearrangements. DNA microarrays were used to determine expression profiles of ALLs and AMLs with ALL-1 rearrangements. These profiles distinguish those tumors from other ALLs and AMLs. The expression patterns of ALL-1-associated tumors, in particular ALLs, involve oncogenes, tumor suppressors, antiapoptotic genes, drug-resistance genes, etc., and correlate with the aggressive nature of the tumors. The genes whose expression differentiates between ALLs with and without ALL-1 rearrangement were further divided into several groups, enabling separation of ALL-1-associated ALLs into two subclasses. One of the groups included 43 genes that exhibited expression profiles closely linked to ALLs with ALL-1 rearrangements. Further, there were evident differences between the expression profiles of AMLs in which ALL-1 had undergone fusion to other genes and AMLs with partial duplication of ALL-1. The extensive analysis described here pinpointed genes that might have a direct role in pathogenesis.C hromosome band 11q23 is a region of recurrent rearrangements in human acute leukemias. These rearrangements, usually in the form of reciprocal chromosome translocations, affect 5-10% of children and adults with acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). The most common translocations are t(4;11) and t(9;11), accounting for 40% and 27%, respectively, of all 11q23 rearrangements. There is a strong association between leukemia phenotype and particular rearrangements. Thus, t(4;11) occurs nearly exclusively in ALL, and 85% of cases with t(9;11) are AMLs (1, 2). Essentially all 11q23 abnormalities involve the ALL-1 gene (also termed MLL, HRX, or HTRX), which rearranges with Ͼ30 partner genes to produce fusion proteins composed of ALL-1 N terminus and the C terminus of the partner protein (3, 4). A second and less frequent type of ALL-1 rearrangement does not involve partner genes but rather partial duplications of ALL-1 N-terminal segments (5). ALL-1-associated leukemias show some unusual and intriguing features (reviewed in refs. 6 and 7). First, they predominate infant acute leukemias, amounting to 80% of infants with ALL and 65% of those with AML. Second, they account for the majority of therapyrelated (secondary) leukemias, developing in 5-15% of primary cancer patients treated with drugs, such as etoposide (VP16), that inhibit DNA topoisomerase II. Third, in infant leukemia and in therapy-related leukemia the disease arises after a brief latency. In fact, studies of monozygotic twins and newborns with leukemia and analysis of neonatal blood spots from children who were diagnosed with leukemia indicate that in most or all infant leukemias ALL-1 rearrangements occur in utero. The short latency suggests that ALL-1 fusion proteins induce leukemia with few, if any, additional mutations. Fourth, prognosis of patients with 11q23 abnormalities is ...

Gene expression analysis reveals a strong signature of an interferon-induced pathway in childhood lymphoblastic leukemia as well as in breast and ovarian cancer

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Pediatric acute lymphoblastic leukemia (ALL) gene expression signatures classify an independent cohort of adult ALL patients

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Smad6 is a protein kinase X phosphorylation substrate and is required for HL-60 cell differentiation

“…The potential partner(s) to which Smad6 may bind in our cells is unknown, so recapitulation of Smad6 DNA binding with purified components in vitro is currently not feasible. However, leukemic cells overexpress a number of Hox gene products (Owens and Hawley, 2002;Rozovskaia et al, 2003). We therefore instead first performed EMSAs on the OPN promoter using HL-60 extracts.…”