On the other hand, a C-terminal truncated AML1 mutant (S291fsX300) induced pancytopenia with erythroid dysplasia in transplanted mice, followed by progression to MDS-RAEB or MDS/AML.
AML1 mutations were identified in 6.3% of AML patients with chromosomal translocations involving CBF, PML-RARalpha, HOX, or ETS transcription factor (TF) gene families.
Quantitation of FLT3 transcript levels revealed a highly significant (P < .001) about 5-fold increase in AML with RUNX1 mutations and trisomy 13 compared with samples without trisomy 13.
AML1-ETO meets JAK2: clinical evidence for the two hit model of leukemogenesis from a myeloproliferative syndrome progressing to acute myeloid leukemia.
Here we report two novel translocations involving the RUNX1 gene: t(1;21)(q12;q22) in a 53-year-old woman with AML-M5b and t(11;21)(q13;q22) in a 65-year-old man with AML-M2.
However, in some families there is transmitted one mutated allele of RUNX1 with no dominant-negative function, demonstrating that simple haploinsufficiency of RUNX1 predisposes to AML and also causes a generalized hematopoietic stem cell disorder most recognizable as thrombocytopenia.
These data suggested that AML1 point mutation is one of the major driving forces of MDS/AML, and these mutations may represent a distinct clinicopathologic-genetic entity.
The morphologic finding of bone marrow in AML-M2 showed higher incidence of Auer rods, large blast with prominent golgi and abnormal granules in AML1/ETO positive patients.
Thirty percent of acute myeloid leukemia cases express a Core Binding Factor (CBF) oncoprotein or harbor point mutations in one or both AML1 (RUNX1) genes.
These observations suggest that reduced AML1 activities predispose cells to the acquisition of the activating FLT3 mutation as a secondary event leading to full transformation in AML M0.
The AML1 (RUNX1)-MTG8 (ETO) fusion transcription factor generated by the t(8;21) translocation is believed to deregulate the expression of genes that are crucial for normal differentiation and proliferation of hematopoietic progenitors, resulting in acute myelogenous leukemia.
Using single-strand conformation polymorphism analysis, we studied the AML1 runt domain in 41 patients with M0 AML and identified potentially pathologic mutations in five (12%).