New mechanisms of AML1 gene alteration in hematological malignancies

Abstract

The human AML1 gene (also named CBFA2 or RUNX1), located in the 21q22 chromosomal band, encodes for one of the two subunits forming a heterodimeric transcription factor, the human core binding factor (CBF). AML1 protein contains a highly evolutionary conserved domain of 128 amino acids called runt domain, responsible for both heterodimerization with the ␤ subunit of CBF and for DNA binding. AML1 is normally expressed in all hematopoietic lineages and acts to regulate the expression of various genes specific to hematopoiesis playing a pivotal role in myeloid differentiation. AML1 is one of the genes most frequently deregulated in leukemia through different mechanisms including translocation, mutation and amplification. Translocations lead to the formation of fusion genes encoding for chimerical proteins such as AML1-ETO which induces leukemogenesis. Recently, new mechanisms of AML1 deregulation by point mutations or amplification have been reported. To our knowledge, 51 patients (among 805 studied) with AML1 point mutations have been described. Forty of them have acute myeloid leukemia (AML) most often M0 AML. In this subtype of AML, the frequency of AML1 mutation is significantly higher; 21.5% of patients mutated (34/158). Mutations have also been found with lower frequency in other FAB subtype AML (6 cases), in myeloproliferative disorders (6 cases), in myelodysplastic syndrome (3 cases) and rarely in acute lymphoblastic leukemia (1 case). AML1 gene amplification has been found essentially in childhood ALL (12 cases) and more rarely in myeloid malignancies (4 cases). Here, we reviewed all these cases of AML1 point mutations and amplification and focused on the mechanisms of AML1 deregulation induced by these alterations.

DNA copy number amplification profiling of human neoplasms

“…The reported amplifications hot spots harbor such amplification-activated oncogenes as EGFR, MYCN, MYC and ERBB2 (Futreal et al, 2004) ( Table 1). The RUNX1 (alias AML1) gene amplification (gene locus 21q22.3 maps to amplification hot spot 27) is typical in a variety of hematologic malignancies (Roumier et al, 2003). 11q23-qter is typically amplified in AML but rarely in other tumors (Zatkova et al, 2004).…”

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

“…125,128 Acquired AML1 mutations observed in other FAB subtypes are often monoallelic and often associated with acquired trisomy 21 or other cytogenetic abnormalities, such as trisomy 13, or with FLT3, P53 or N-RAS mutations. 133,134 Interestingly, in patients with constitutional trisomy 21 (that is, Down syndrome), who have a propensity to develop AML, no AML1 mutations have been found. Copy number variation of the AML1 gene could be presompted to participate to leukemogenesis both by increase or defect.…”

CEBPA point mutations in hematological malignancies

“…It has previously been reported that biallelic mutations of another early myeloid differentiation gene (AML1/ RUNX1) could induce M0 AML subtype. 2 Furthermore, mice models of CML blast crisis with CEBPA knockout result in immature erythroid leukemia 30,31 and expression of a dominant negative 30-kDa CEBPA protein inhibits differentiation of myeloid and erythroid progenitors. 32 On the other hand, all CEBPAmutated patients reviewed in this work had M1, M2, M4 or M5 AML subtypes, clearly showing persistence of myeloid differentiation in blast cells.…”

“…1 In acute myeloid leukemia (AML), cell differentiation arrest can occur at different levels by alteration of specific genes like those of the CBF complex. 2 The CEBPA gene (located on chromosome 19q13.1 band) belongs to the CCAAT/enhancer-binding protein family, which is involved in the balance between cell proliferation and terminal differentiation. CEBPA gene mRNA can be translated from the first AUG encoding the 42-kDa normal isoform and also from the second AUG (nt 508-510) encoding the 30-kDa normal isoform, which has lost the 119 first AA including the TAD1 functional domain.…”