AbstractBACKGROUND: The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFb, is essential for normal hematopoiesis. Recent studies have shown that mutations and gene rearrangements involving this complex are frequently implicated in leukemogenesis. Understanding the molecular events leading to the disruption of CBF has provided important insights into our understanding of the normal regulatory pathways that control hematopoiesis and has begun to reveal how alterations in these pathways induce leukemia. INFORMATION SOURCES: Both authors are involved in the identification and characterization of chromosomal abnormalities associated with hematologic malignancy. This has led to contributions to multicenter clinical and laboratory investigations as well as publications in peer-reviewed journals. All of the references cited in this review are published in journals covered by Medline. State of the Art. The core binding factor (CBF) is a heterodimeric transcription factor composed of the RUNX1 and CBFb subunits. RUNX1 is the DNA binding element of the complex and its affinity is greatly increased in the presence of CBFb. Knock-out studies in mice have demonstrated that both RUNX1 and CBFb are necessary for definitive hematopoiesis. Furthermore, reciprocal chromosomal translocations involving both partners have been directly implicated in leukemogenesis. Evidence is now emerging that at least some of the resulting fusion proteins, namely ETV6-RUNX1, RUNX1-MTG8 and CBFb-MYH11 dominantly inhibit the function of native CBF by recruiting transcriptional co-repressor complexes. However, knock-in studies have shown that whilst expression of these fusion genes may disrupt normal hematopoiesis, this, by itself, is not sufficient for the subsequent development of leukemia. Mutations of RUNX1 have been identified in familial platelet disorder (FDP), in which there is a congenital predisposition to the development of AML and heterozygous point mutations have been identified in the RUNX1 gene in some leukemias. Moreover, a small number of cases have been reported in which amplification of RUNX1 has been detected in childhood ALL suggesting mechanisms other than loss of function, such as gene dosage may also play a role. CONCLUSIONS: Understanding the role CBF plays in normal hematopoiesis and hematologic malignancies has provided critical reagents for the accurate identification of the broad group of leukemias harboring alterations of CBF. The application of these molecular approaches has already shown an impact on the clinical management of these patients and as more information becomes available, the ability to tailor therapy to improve each patient's chance of a cure becomes feasible.
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Vol. 87 No. 12 (2002): December, 2002 : Articles
Ferrata Storti Foundation, Pavia, Italy
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