An update on the molecular pathogenesis and potential therapeutic targeting of AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1

被引:74
作者
Al-Harbi, Sayer [1 ]
Aljurf, Mahmoud [2 ]
Mohty, Mohamad [3 ]
Almohareb, Fahad [2 ]
Ahmed, Syed Osman Ali [2 ]
机构
[1] King Faisal Specialist Hosp & Res Ctr, Oncol Ctr, Dept Mol Oncol, Res Ctr, Riyadh, Saudi Arabia
[2] King Faisal Specialist Hosp & Res Ctr, Oncol Ctr, Adult Hematol Bone Marrow Transplantat, MBC 64,Rob 3354, Riyadh 11211, Saudi Arabia
[3] Sorbonne Univ, Hop San Antoine, AP HP, INSERM,Unite Mixte Rech 938, Paris, France
关键词
ACUTE MYELOID-LEUKEMIA; AMYLOID PRECURSOR PROTEIN; MINIMAL RESIDUAL DISEASE; C-KIT MUTATIONS; FUSION PROTEINS; TRANSCRIPTIONAL REPRESSION; SELF-RENEWAL; DNA-DAMAGE; AML1-ETO; T(8/21);
D O I
10.1182/bloodadvances.2019000168
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Acute myeloid leukemia (AML) with t(8:21)(q22;q22.1);RUNX1-RUNX1T1, one of the core binding factor leukemias, is one of the most common subtypes of AML with recurrent genetic abnormalities and is associated with a favorable outcome. The translocation leads to the formation of a pathological RUNX1-RUNX1 Ti fusion that leads to the disruption of the normal function of the core-binding factor, namely, its role in hematopoietic differentiation and maturation. The consequences of this alteration include the recruitment of repressors of transcription, thus blocking the expression of genes involved in hematopoiesis, and impaired apoptosis. A number of concurrent and cooperating mutations clearly play a role in modulating the proliferative potential of cells, including mutations in KIT, FLT3, and possibly JAK2. RUNX1-RUNX1T1 also appears to interact with microRNAs during leukemogenesis. Epigenetic factors also play a role, especially with the recruitment of histone deacetylases. A better understanding of the concurrent mutations, activated pathways, and epigenetic modulation of the cellular processes paves the way for exploring a number of approaches to achieve cure. Potential approaches include the development of small molecules targeting the RUNX1-RUNX1T1 protein, the use of tyrosine kinase inhibitors such as dasatinib and FLT3 inhibitors to target mutations that lead to a proliferative advantage of the leukemic cells, and experimentation with epigenetic therapies. In this review, we unravel some of the recently described molecular pathways and explore potential therapeutic strategies.
引用
收藏
页码:229 / 238
页数:10
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