Thus, loss of p21(WAF1) facilitates AML1-ETO-induced leukemogenesis, suggesting that mutagenic events in the p21(WAF1) pathway to bypass the growth inhibitory effect from AML1-ETO-induced p21(WAF1) expression can be a significant factor in AML1-ETO-associated acute myeloid leukemia.
Taken together, these data support the notion that VPA might effectively target AML1/ETO-driven leukemogenesis through disruption of aberrant HDAC1 function and that VPA should be integrated in novel therapeutic approaches for AML1/ETO-positive AML.
These common elements in gene expression profiles between t(8;21)- and inv(16)-AML probably reflect the situation that AML1-MTG8 and CBFbeta-MYH11 chimaeric proteins affect a common set of target genes in CBF leukaemic cells.
For example, whereas the E2A portion of the E2A-Pbx1 leukemia fusion protein mediates robust transcriptional activation in t(1;19) acute lymphoblastic leukemia, the transcriptional activity of wild-type E2A is silenced by high levels of corepressors, such as the AML1-ETO fusion protein in t(8;21) acute myeloid leukemia and ETO-2 in hematopoietic cells.
Morphological characteristics, cytogenetic profile, and outcome of RUNX1-RUNX1T1-positive acute myeloid leukemia: Experience of an Indian tertiary care center.
Acute myeloid leukemia (AML) arises from genetic changes at the level of stem cell, various mutations have been elucidated, including AML1-ETO fusion gene has been shown as the representative target of cellular transformation for LSCs originating from hematopoietic stem cells (HSCs) compartment.
In t(8;21) acute myelogenous leukemia (AML), the AML1 gene is juxtaposed to the ETO gene located on chromosome 8, generating an AML1/ETO fusion protein.
All these results suggested that OA might be a novel candidate agent for differentiation therapy for AML1/ETO-positive AML and the mechanism required further investigation.
The dominant negative characteristics of AML1/ETO may be important for AML pathogenesis and may provide a molecular target for therapeutic intervention.
Outside of signaling alterations, RUNX1-RUNX1T1 and CBFB-MYH11 AMLs demonstrated remarkably different spectra of cooperating mutations, as RUNX1-RUNX1T1 cases harbored recurrent mutations in DHX15 and ZBTB7A, as well as an enrichment of mutations in epigenetic regulators, including ASXL2 and the cohesin complex.
The former type is associated with the chromosomal translocations found in acute myeloid leukemia, such as the AML1/MTG8 in t(8;21) and PML/RAR alpha in t(15;17).
The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases.
We analyzed the activity of the histone deacetylase inhibitor (HDACi) suberoyl-anilide hydroxamic acid (SAHA) on Kasumi-1 acute myeloid leukemia (AML) cells expressing AML1/ETO.
The activation of B-cell-specific genes, such as CD19 and PAX5, is a hallmark of t(8;21) acute myeloid leukemia (AML) which expresses the translocation product RUNX1/ETO.
Knockdown of UbcH8 by small hairpin RNAs (shRNAs) prevented HNK-induced degradation of AML-ETO, suggesting that UbcH8 plays a critical role in the degradation of AML1-ETO.
This finding increases our understanding of the mechanisms by which the AML1/ETO protein may contribute to modified gene expression linked to the onset and progression of t(8;21) related acute myelogenous leukemia.
Some recurrent aberrations and the resulting gene rearrangements, namely inv(16)/t(16;16) and CBFbeta- MYH11, t(8;21) and CBFA2-CBFA2T1, t(15;17) and PML-RARalpha, and rearrangements of band 11q23 and the MLL gene, are now used to help define distinct disease entities within AML in the new World Health Organization classification of haematological malignancies.
The chromosomal translocation t(8;21), generating the AML1-ETO fusion protein, is frequently associated with French-American-British (FAB) type M2 acute myeloid leukemia (AML). t(8;21) fuses the runt domain from the hematopoietic transcription factor RUNX1 with almost the entire transcriptional repressor ETO.