Molecular pathogenesis of core binding factor leukemia: current knowledge and future prospects

Abstract

Core binding factor (CBF) acute myeloid leukemia (AML) is the most common cytogenetic subtype of AML, defined by the presence of t(8;21) or inv(16)/t(16;16). The chromosomal aberrations create AML1-ETO and CBFβ-MYH11 fusion genes that disrupt the functions of CBF, an essential transcription factor in hematopoiesis. Despite the relatively good outcome of patients with CBF-AML, only approximately half of the patients are cured with current therapy, indicating the need for improved therapeutic strategies. In this review, we summarize current knowledge regarding altered transcriptional regulation, aberrant signaling pathways, and cooperating genetic events in CBF leukemia, and discuss challenges ahead for translating these findings into the clinic.

Down-regulated MYH11 Expression Correlates with Poor Prognosis in Stage II and III Colorectal Cancer

“…Myosins have a well-characterized biological function in using the energy of ATP hydrolysis to move actin filaments to produce muscle force. For so long, the researches about MYH11 have been concentrated on acute myeloid leukemia (AML), because MYH11 has been involved in the composition of fusion gene CBFβ-MYH11, and CBFβ will generally form an intranuclear transcriptionally active complex together with RUNX1, so the fusion gene disturb the function of CBFβ, which influences hematopoiesis (Goyama and Mulloy, 2011). However, recently myosins are implicated also in a variety of other cellular function and many of which are relevant for cancer formation (Krendel and Mooseker, 2005).…”

Abrogation of RUNX1 gene expression in de novo myelodysplastic syndrome with t(4;21)(q21;q22)

“…To explain this lack of expression, we examined whether RUNX1 had been inactivated through point mutations, since it has been reported to be an important pathogenic mechanism in AML and MDS. We amplified and RUNX1 abrogation in MDS haematologica | 2012; 97 (4)sequenced all RUNX1 exons in one single PCR and found no mutations in the retained RUNX1 allele. We then decided to explore epigenetic inactivation by assessing the methylation status of its promoter region.…”

“…This and other variant fusion proteins involving RUNX1 always lose their transactivation potential, resulting in a disruption of the normal hematopoietic differentiation program secondary to a wild-type RUNX1 haploinsufficiency. 4 On a clinical level, RUNX1 mutations are more likely to occur in patients with secondary exposure-related MDS (t-MDS) due to a mutagenic effect of the chemotherapy or ionizing radiation and its association with a worse prognosis has been established. 3 In summary, the disruption of RUNX1 function is one of the main mechanisms of disease observed in hematopoietic malignancies and the development of genomic technologies has allowed novel genetic events that lead to a RUNX1 loss of function to be identified and described.…”

The Association between mrna Expression Levels of Ephx1 and Prognosis of Acute Myeloid Leukemia

“…Diagnosis rests on demonstration that the marrow or blood has>20% blasts with specifical surface markers CD33 and CD13 [1]. Approximately 10% of AML are classified as having core binding factor (CBF) leukemia with a heterodimeric transcription factor complex comprising RUNX1(AML1, CBFα) and CBFβ, which plays a critical role in hematopoiesis [2]. The standard therapy for AML over the past 30 years has been centered on the traditional"7+3" regimen consisting of daunorubicin, administer over 3 days alongside cytarabine, administered over 7 days [1].…”