Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells

Luedtke, Daniel A; Niu, Xuming; Pan, Yihang; Zhao, Jianyun; Liu, Shuang; Edwards, Holly; Chen, Kang; Lin, Hai; Taub, Jeffrey W.; Ge, Yubin

doi:10.1038/sigtrans.2017.12

Cited by 108 publications

(99 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Having observed the synergy between ABT‐199 and KPT‐330, we sought out to determine how the combination treatment affected levels of relevant Bcl‐2 family proteins. In agreement with our previous studies, Mcl‐1 levels increased in response to ABT‐199 treatment in the ABT‐199‐resistant cell lines (THP‐1 and OCI‐AML3), but not in the ABT‐199‐sensitive cell line MV4‐11 (Figure A) . In support of our hypothesis, KPT‐330 treatment decreased Mcl‐1 levels and was able to prevent up‐regulation of Mcl‐1 induced by ABT‐199.…”

Section: Resultssupporting

confidence: 92%

“…14,22 Furthermore, We previously demonstrated that the Mcl-1 small molecule inhibitor A-1210477 was able to synergize with ABT-199 to induce apoptosis in AML cell lines and primary patient samples by disrupting the Bim-Mcl-1 interaction. 23 However, the drug combination also synergized to reduce proliferation of normal peripheral blood mononuclear cells (PMNCs), albeit at higher concentrations. Thus, indirect inhibition of Mcl-1 may prove to be useful in combination with ABT-199.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1

Luedtke

Liu

et al. 2018

J Cellular Molecular Medi

Self Cite

View full text Add to dashboard Cite

The antiapoptotic Bcl‐2 family proteins play critical roles in resistance to chemotherapy in acute myeloid leukaemia (AML). The Bcl‐2‐selective inhibitor ABT‐199 (Venetoclax) shows promising antileukaemic activity against AML, though Mcl‐1 limits its antileukaemic activity. XPO1 is a nuclear exporter overexpressed in AML cells and its inhibition decreases Mcl‐1 levels in cancer cells. Thus, we hypothesized that the XPO1‐selective inhibitor KPT‐330 (Selinexor) can synergize with ABT‐199 to induce apoptosis in AML cells through down‐regulation of Mcl‐1. The combination of KPT‐330 and ABT‐199 was found to synergistically induce apoptosis in AML cell lines and primary patient samples and cooperatively inhibit colony formation capacity of primary AML cells. KPT‐330 treatment decreased Mcl‐1 protein after apoptosis initiation. However, binding of Bim to Mcl‐1 induced by ABT‐199 was abrogated by KPT‐330 at the same time as apoptosis initiation. KPT‐330 treatment increased binding of Bcl‐2 to Bim but was overcome by ABT‐199 treatment, demonstrating that KPT‐330 and ABT‐199 reciprocally overcome apoptosis resistance. Mcl‐1 knockdown and overexpression confirmed its critical role in the antileukaemic activity of the combination. In summary, KPT‐330 treatment, alone and in combination with ABT‐199, modulates Mcl‐1, which plays an important role in the antileukaemic activity of the combination.

show abstract

Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1

Luedtke

Liu

et al. 2018

J Cellular Molecular Medi

Self Cite

View full text Add to dashboard Cite

show abstract

“…These surprising results in the mouse suggest that AML or a fraction of AML in humans could be caused by the overexpression of direct and indirect targets of miR-15/16, caused by the loss of these two miRNA clusters. In this case, treatment of these AML, driven by the loss of miR-15/ 16 clusters, could take advantage of the new anti-Bcl-2 drug venetoclax and of monoclonal antibodies against ROR1, a surface antigen regulated, like Bcl-2, by miR-15/16 and of future anti-Mcl-1 small molecules (18). Mcl-1 has been found to be frequently overexpressed in AML (19).…”

Section: Discussionmentioning

confidence: 99%

Knockout of both miR-15/16 loci induces acute myeloid leukemia

Lovat

Fassan

Sacchi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

MicroRNAs (miRNAs) have been extensively reported to be associated with hematological malignancies. The loss of miR-15a/16-1 at chromosome 13q14 is a hallmark of most of human chronic lymphocytic leukemia (CLL). Deletion of murine miR-15a/16-1 and miR-15b/ 16-2 has been demonstrated to promote B cell malignancies. Here, we evaluate the biological role of miR-15/16 clusters, crossbreeding miR-15a/16-1 and miR-15b/16-2 knockout mice. Unexpectedly, the complete deletion of both clusters promoted myeloproliferative disorders in the majority of the mice by the age of 5 months with a penetrance of 70%. These mice showed a significant enlargement of spleen and abnormal swelling of lymph nodes. Flow cytometry characterization demonstrated an expanded CD11b/Gr-1 double-positive myeloid population both in spleen and in bone marrow. The transplantation of splenocytes harvested from double-KO mice into wildtype recipient mice resulted in the development of myeloproliferative disorders, as observed in the donors. In vivo, miR-15/16 cluster deletion up-regulated the expression of Cyclin D1, Cyclin D2, and Bcl-2. Taken together, our findings identify a driver oncogenic role for miR-15/16 cluster deletion in different leukocytic cell lineages. miR-15/16 cluster | acute myeloid leukemia | mouse model T he loss of miR-15a/16-1 at chromosome 13q14, encoding two miRNAs residing in the same polycistrocnic RNA, is a hallmark of most of human chronic lymphocytic leukemias (CLL) (1). This dysregulation has been proved as the first evidence that genetic alteration in noncoding genes can cause malignancy (1).Most of CLLs are indolent but may progress to an aggressive disease. Analysis for mutations in many CLL showed that germline mutations just seven nucleotides 3′ of miR-16-1 are present in familial CLL (2), and this region was found to be necessary for processing of the miRNA precursor (3). Furthermore, the mouse strain NZB that develops an indolent CLL late in life carries a mutation six nucleotides 3′ of miR-16-1 affecting miR-15/16 processing, indicating that loss of function of miR-15a/16-1 leads to the development of indolent CLL (4). The frequency of loss of one or both miR-15a/16-1 clusters on chromosome 13q14 occurs in over 70% of the CLL patients and is the most common genetic alteration in CLL (1). Klein et al. (5) knocked out the miR-15a/16-1 locus in the mouse, and the knockout (KO) mice developed late in life the indolent form of CLL, as in human patients (6). Thus, loss of miR-15a/16-1 leads to the development of indolent CLL both in humans and mice. Since an additional locus of miR-15/16 exists on chromosome 3 (3q25), we have knocked out this second miR-15b/16-2 locus in the mouse (7). These mice developed mainly CLL and few diffuse large B cell lymphoma at higher penetrance (60%) and earlier age at 15-18 months (7) than the miR-15a/16-1 KO mice described by Klein et al. (5). Here, we evaluated the biological role of two different miR-15/16 clusters, crossbreeding miR-15a/16-1 and miR-15b/16-2 knockout (KO) mice. Unexpec...

show abstract

“…Luedtke et al investigated the activity of A-1210477, alone or in combination with venetoclax, and observed synergistic induction of apoptosis both in AML cell lines and in patient-derived samples, secondary to decreased MCL-1 mediated sequestration of BIM. 46 Ramsey et al showed that VU661013 destabilized the association between BIM and MCL-1, leading to apoptosis in venetoclax-resistant AML cells and patientderived xenografts, and showed significant activity in murine models of AML in combination with venetoclax. 47 Similar results were reported by Caenepeel et al, who showed that AMG176 was synergistic in combination with venetoclax in AML tumor models and in primary patient samples.…”

Section: Combination Strategies To Boost Venetoclax Activity and Overmentioning

confidence: 99%

Venetoclax for AML: changing the treatment paradigm

Pollyea

Amaya

Strati³

et al. 2019

Blood Advances

129

View full text Add to dashboard Cite

Venetoclax is a specific B-cell lymphoma-2 (BCL-2) inhibitor that can restore activation of apoptosis in malignancies, the survival of which depends on dysregulation of this pathway.Preclinical data, using various model systems including cell lines and patient samples, suggested targeting BCL-2 could be a successful therapeutic strategy in patients with acute myeloid leukemia (AML). As predicted by this work, the use of venetoclax in the clinical setting has resulted in promising outcomes for patients with this disease. Although venetoclax showed limited activity as a single agent in the relapsed disease setting, recent studies have shown that when combined with a backbone therapy of a hypomethylating agent or low-dose cytarabine, high response rates with encouraging remission durations for older patients with newly diagnosed AML who were not candidates for intensive induction chemotherapy were observed. Furthermore, venetoclax-based therapies allowed for rapid responses and were able to effectively target the leukemia stem cell population. Here we review the preclinical data that supported the development of venetoclax in AML, as well as the results of the promising clinical trials. Preclinical development The intrinsic apoptotic pathwayThe B-cell lymphoma-2 (BCL-2) family includes multiple proteins sharing BCL-2-like homology domains 1-4 (BH1-BH4), each playing a specific role in the intrinsic apoptotic pathway. The BCL-2 family proteins' roles can be divided into 4 main functions: suppressors (BCL-2, BCL-XL, BCL-W, BCL2-A1, and MCL-1), activators (BIM and PUMA), effectors (BAX and BAK), and sensitizers (NOXA). 8,9 Suppressors inhibit the activity of activators and effectors, preventing apoptosis, whereas sensitizers inhibit suppressors, releasing the brake on activators and effectors. The latter oligomerize, creating

show abstract

Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells

Cited by 108 publications

References 36 publications

Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1

Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1

Knockout of both miR-15/16 loci induces acute myeloid leukemia

Venetoclax for AML: changing the treatment paradigm

Contact Info

Product

Resources

About