Abstract
The treatment of chronic myeloid leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, has yielded clinical success. However, the direct targeting of BCR-ABL does not eradicate CML cells expressing mutant BCR-ABL, especially the T315I mutation in BCR-ABL. Moreover, increasing mutations were identified in BCR-ABL domain, resulting in TKIs resistance recently. It is necessary to find BCR-ABL-independent target for treating CML patients with various mutations, including T315I mutation in BCR-ABL. The dichotomous behavior of CREB binding protein (CBP) and E1A protein (p300), recruited by β-catenin associated with self-renewal and differentiation, have been identified in hematopoietic stem cells, respectively. In this study, CBP was aberrantly expressed in CML cells on the basis of Oncomine dataset. The β-catenin bound with much more CBP than p300 in CML cells. Down-regulation of CBP inhibited cell proliferation capacity and increased the binding of β-catenin to p300, thus promoting cell differentiation and p53-dependent cell senescence in CML cells with either wild type or T315I mutant BCR-ABL in vitro and in vivo models. These demonstrate CBP blockage can be developed for the treatment of CML independent of BCR-ABL mutation status including T315I.
Highlights
Chronic myeloid leukemia (CML) is a clonal malignant disorder of pluripotent hematopoietic stem cells (HSCs), characterized by the presence of Philadelphia chromosome (Ph) translocation t(9;22) (q34;q11), leading to the formation of the novel BCR-ABL fusion gene [1]
Silence of p300 did not change the differentiate ratio compared with the scramble cells, implying that silencing endogenous CREB banding protein (CBP) rather than p300 have the significant potential to promote cell differentiation in CMLs independent of BCR-ABL mutation status
We found that the knockdown of CBP decreased the expression of cyclinD1 which was one of the downstream molecules of b-catenin/CBP, but concomitantly increased the expression level of JUN which was a downstream molecule of b-catenin/p300, independent of the mutation status of BCR-ABL in CML cells (Figure 3A)
Summary
Chronic myeloid leukemia (CML) is a clonal malignant disorder of pluripotent hematopoietic stem cells (HSCs), characterized by the presence of Philadelphia chromosome (Ph) translocation t(9;22) (q34;q11), leading to the formation of the novel BCR-ABL fusion gene [1]. Despite BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, and dasatinib, have been developed, a significant number of patients develop resistance to treatment overtime [2, 3]. The most frequent mechanism producing resistance is the increasing kinase domain mutations, notably the T315I b-Catenin/p300 Activation for CMLs Treatment mutation, which reduces or completely ablates drug efficacy [4,5,6,7]. Increasing new mutations have been discovered in BCR-ABL kinase domain, leading to TKIs resistance. The activation of Wnt/b-catenin pathway recruits CREB banding protein (CBP) or E1A protein (p300) triggering cell self-renewal and differentiation in HSC, respectively [8, 10, 14]. We deduced that the effective inhibition of CBP might disrupt the ectopic balance between bcatenin/CBP and b-catenin/p300 complexes and result in cell differentiation and senescence in CML
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