Browsing by Author "Chen, Shu-Huey"

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ABLGenomic Editing Sufficiently Abolishes Oncogenesis of Human Chronic Myeloid Leukemia Cells In Vitro and In Vivo
(2020-06-01)
Chen, Shu-Huey
;
Hsieh, Yao-Yu
;
Tzeng, Huey-En
;
Lin, Chun-Yu
;
Hsu, Kai-Wen
Chronic myelogenous leukemia (CML) is the most common type of leukemia in adults, and more than 90% of CML patients harbor the abnormal Philadelphia chromosome (Ph) that encodes the BCR-ABL oncoprotein. Although the ABL kinase inhibitor (imatinib) has proven to be very effective in achieving high remission rates and improving prognosis, up to 33% of CML patients still cannot achieve an optimal response. Here, we used CRISPR/Cas9 to specifically target theBCR-ABLjunction region in K562 cells, resulting in the inhibition of cancer cell growth and oncogenesis. Due to the variety ofBCR-ABLjunctions in CML patients, we utilized gene editing of the humanABLgene for clinical applications. Using theABLgene-edited virus in K562 cells, we detected 41.2% indels inABLsgRNA_2-infected cells. TheABL-edited cells reveled significant suppression of BCR-ABL protein expression and downstream signals, inhibiting cell growth and increasing cell apoptosis. Next, we introduced theABLgene-edited virus into a systemic K562 leukemia xenograft mouse model, and bioluminescence imaging of the mice showed a significant reduction in the leukemia cell population inABL-targeted mice, compared to the scramble sgRNA virus-injected mice. In CML cells from clinical samples, infection with theABLgene-edited virus resulted in more than 30.9% indels and significant cancer cell death. Notably, no off-target effects or bone marrow cell suppression was found using theABLgene-edited virus, ensuring both user safety and treatment efficacy. This study demonstrated the critical role of theABLgene in maintaining CML cell survival and tumorigenicity in vitro and in vivo.ABLgene editing-based therapy might provide a potential strategy for imatinib-insensitive or resistant CML patients.
HDAC1,2 Knock-Out and HDACi Induced Cell Apoptosis in Imatinib-Resistant K562 Cells
(2019-05-01)
Chen, Shu-Huey
;
Chow, Jyh-Ming
;
Hsieh, Yao-Yu
;
Lin, Chun-Yu
;
Hsu, Kai-Wen
Since imatinib (Glivec or Gleevec) has been used to target the BCR-ABL fusion protein, chronic myeloid leukemia (CML) has become a manageable chronic disease with long-term survival. However, 15%-20% of CML patients ultimately develop resistance to imatinib and then progress to an accelerated phase and eventually to a blast crisis, limiting treatment options and resulting in a poor survival rate. Thus, we investigated whether histone deacetylase inhibitors (HDACis) could be used as a potential anticancer therapy for imatinib-resistant CML (IR-CML) patients. By applying a noninvasive apoptosis detection sensor (NIADS), we found that panobinostat significantly enhanced cell apoptosis in K562 cells. A further investigation showed that panobinostat induced apoptosis in both K562 and imatinib-resistant K562 (IR-K562) cells mainly via H3 and H4 histone acetylation, whereas panobinostat targeted cancer stem cells (CSCs) in IR-K562 cells. Using CRISPR/Cas9 genomic editing, we found that HDAC1 and HDAC2 knockout cells significantly induced cell apoptosis, indicating that the regulation of HDAC1 and HDAC2 is extremely important in maintaining K562 cell survival. All information in this study indicates that regulating HDAC activity provides therapeutic benefits against CML and IR-CML in the clinic.