A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL-AF9, MLL-AF4, and AML1-ETO.
Although alterations of gene expression and hematopoietic cell proliferation have been reported in the presence of AML1-ETO, its expression does not lead to the development of leukemia.
AML1-ETO fusion protein is a product of chromosome translocation t(8;21) frequently occurred in acute myeloid leukemia (AML), but its sole expression appears to fail to cause overt leukemia in vivo.
AML1-ETO-W692A loses N-CoR binding at NHR4, displays attenuated transcriptional repression ability and decreased cellular dysregulation, and promotes leukemia in vivo.
AML1/ETO-positive leukemia shows specific mechanism of VPA residing from differentiation followed by apoptosis that is accompanied by an increase in the expression of repressed AML1 target genes.
AML1/ETO fusion transcripts were neither found in the PB and BM of a healthy individual, nor in the PB of a patient after allogeneic BMT for cytogenetically proven t(8;21)-leukemia.
Analysis of patient's primary leukemia blasts revealed that those carrying the t(8;21) generating AML1/ETO, the most common acute myeloid leukemia-associated fusion protein, display low levels of a microRNA-223 (miR-223), a regulator of myelopoiesis.
Areas covered: Available techniques include multi-color flow cytometry (MFC) of leukemia associated immunophenotypes (LAIP), quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) for detecting fusion and mutated genes (RUNX1-RUNX1T1, CBFB-MYH11, and NPM1), overexpression of genes such as WT1, and next generation sequencing (NGS) for MRD.
Association of MTG8 (ETO/CDR), a leukemia-related protein, with serine/threonine protein kinases and heat shock protein HSP90 in human hematopoietic cell lines.
BAL with t(8; 21)(q22; q22) might be a new subgroup of BAL, and it was suggested that the leukemia clone with t(8;21)(q22;q22) might have originated from an early phase of hematopoiesis, and AML1/ETO fusion gene might be related to differentiation of B lymphocyte.
Because the PCR detection of the AML1/MTG8(ETO) fusion at the RNA level is highly sensitive, it can be used as a sensitive method for diagnosis and detection of minimal residual disease in t(8;21) leukemia.
By focusing on the anti-apoptotic gene Bcl-2, the key regulator gene of granulocytic differentiation CCAAT/enhancer-binding protein α (CEBPA) and the tumor suppressor gene p14(ARF), we found that both AML1-ETO-expressing cell lines and t(8;21) leukemia samples displayed low levels of these three genes.
Despite numerous studies on the function of AML1-ETO, the precise mechanism by which the fusion protein is involved in leukemia development is still not fully understood.
Experimental data have shown that AML1-ETO is not sufficient to induce leukemia by itself, but has to collaborate with other genetic alterations for leukemic transformation.
Further investigations on the potential in vivo effects of such a cleavage and its possible role in leukemogenesis would provide new insights for understanding the biology and treatment of AML1-ETO-associated leukemia.
Here, we report that disruption of the zinc-chelating structure in the NHR4 domain of AML1-ETO by replacing only one critical amino acid leads to rapid onset of leukemia, demonstrating that the NHR4 domain with the intact structure generates inhibitory effects on leukemogenesis.
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.