Loss of MXD3 induces apoptosis of Reh human precursor B acute lymphoblastic leukemia cells

Barisone, Gustavo A.; Satake, Noriko; Lewis, Carly; Duong, Connie P.M.; Chen, Cathy; Lam, Kit S.; Nolta, Jan A.; Díaz, Elizabeth

doi:10.1016/j.bcmd.2014.12.002

Cited by 21 publications

(26 citation statements)

References 21 publications

(26 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The mechanism of action of the αCD22-ASO conjugate remains unclear since the rapid kinetics of MXD3 protein knockdown is not consistent with inhibition of MXD3 mRNA levels (data not shown). Interestingly, the same phenomenon (early MXD3 protein knockdown without confirmation of mRNA knockdown) was observed with several different MXD3 ASO sequences (data not shown), as well as MXD3 siRNA (47,48), with or without αCD22 Ab as a vehicle. These data suggest that the ASO conjugate may mediate MXD3 translational inhibition and thus would explain the inability to detect a reduction in MXD3 transcript levels (59,60).…”

Section: Acknowledgmentssupporting

confidence: 68%

“…MAX dimerization protein 3 (MXD3) is a basic-helix-loop-helix-leucine-zipper transcription factor that is part of the v-myc avian myelocytomatosis viral oncogene homolog (MYC)/MAX/MXD transcriptional network involved in cellular proliferation (44)(45)(46). Previously, we demonstrated that MXD3 functions as an anti-apoptotic protein and that knockdown of MXD3 can be a novel effective therapeutic strategy for preB ALL in vitro (47,48). In this study, we developed a novel leukemia-targeting compound using MXD3 ASO conjugated to anti-CD22 Ab (αCD22 Ab) for preB ALL.…”

Section: Cd22 Ab-aso Conjugatementioning

confidence: 99%

See 1 more Smart Citation

Novel Targeted Therapy for Precursor B-Cell Acute Lymphoblastic Leukemia: Anti-CD22 Antibody-MXD3 Antisense Oligonucleotide Conjugate

Satake

Duong

Yoshida

et al. 2016

Mol Med

Self Cite

View full text Add to dashboard Cite

The exponential rise in molecular and genomic data has generated a vast array of therapeutic targets. Oligonucleotide-based technologies to down regulate these molecular targets have promising therapeutic efficacy. However, there is relatively limited success in translating this into effective in vivo cancer therapeutics. The primary challenge is the lack of effective cancer cell-targeted delivery methods, particularly for a systemic disease such as leukemia. We developed a novel leukemiatargeting compound composed of a monoclonal antibody directly conjugated to an antisense oligonucleotide (ASO). Our compound uses an ASO that specifically targets the transcription factor MYC-associated factor X (MAX) dimerization protein 3 (MXD3), which was previously identified to be critical for precursor B-cell (preB) acute lymphoblastic leukemia (ALL) cell survival. The MXD3 ASO was conjugated to an anti-cluster of differentiation-22 (CD22) antibody (αCD22 Ab) that specifically targets most preB ALL. We demonstrated that the αCD22 Ab-ASO conjugate treatment showed MXD3 protein knockdown and leukemia cell apoptosis in vitro. We also demonstrated that the conjugate treatment showed cytotoxicity in normal B cells, but not in other hematopoietic cells, including hematopoietic stem cells. Furthermore, the conjugate treatment at the lowest dose tested (0.2 mg/kg Ab for 6 doses -twice a week for 3 wks) more than doubled the mouse survival time in both Reh (median survival time 20.5 versus 42.5 d, p < 0.001) and primary preB ALL (median survival time 29.3 versus 63 d, p < 0.001) xenograft models. Our conjugate that uses αCD22 Ab to target the novel molecule MXD3, which is highly expressed in preB ALL cells, appears to be a promising novel therapeutic approach.

show abstract

Section: Acknowledgmentssupporting

confidence: 68%

Section: Cd22 Ab-aso Conjugatementioning

confidence: 99%

Novel Targeted Therapy for Precursor B-Cell Acute Lymphoblastic Leukemia: Anti-CD22 Antibody-MXD3 Antisense Oligonucleotide Conjugate

Satake

Duong

Yoshida

et al. 2016

Mol Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…To confirm that the higher levels of apoptosis we observed were indeed due to MXD3 knockdown and not off-target effects, we tested the treatment on SK-N-DZ cells expressing a rescue construct coding for knockdown-insensitive, wild-type MXD3 ( 9 ). SK-N-DZ cells were stably transduced using lentiviral vectors expressing MXD3 shRNA and the rescue sequence (shMXD3Rescue), MXD3 shRNA alone (shMXD3), or a negative control shRNA (shControl) designed to not knockdown any known human gene.…”

Section: Resultsmentioning

confidence: 91%

“…Since monotherapy does not work for most cancers, an ideal therapy should include multiple molecular-targeted approaches. Previously, we identified the transcription factor MXD3 as a novel target for precursor B-cell acute lymphoblastic leukemia (preB ALL) ( 9 – 11 ). MXD3 is a member of the family of Mad proteins that interact with Max proteins ( 12 ) and is reported to play a role in medulloblastoma tumorigenesis ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Novel targeted therapy for neuroblastoma: silencing the MXD3 gene using siRNA

et al. 2017

Self Cite

View full text Add to dashboard Cite

BackgroundNeuroblastoma is the second most common extracranial cancer in children. Current therapies for neuroblastoma, which use a combination of chemotherapy drugs, have limitations for high-risk subtypes and can cause significant long-term adverse effects in young patients. Therefore, a new therapy is needed. In this study, we investigated the transcription factor MXD3 as a potential therapeutic target in neuroblastoma.MethodsMXD3 expression was analyzed in five neuroblastoma cell lines by immunocytochemistry and quantitative real time reverse transcription PCR and in 18 primary patient tumor samples by immunohistochemistry. We developed nanocomplexes using siRNA and superparamagnetic iron oxide nanoparticles to target MXD3 in neuroblastoma cell lines in vitro as a single agent therapeutic and in combination with doxorubicin, vincristine, cisplatin, or maphosphamide, common drugs used in current neuroblastoma treatment.ResultsMXD3 was highly expressed in neuroblastoma cell lines and in patient tumors that had high-risk features. Neuroblastoma cells treated in vitro with the MXD3 siRNA nanocomplexes showed MXD3 protein knockdown and resulted in cell apoptosis. Furthermore, combining MXD3 siRNA nanocomplexes with each of the four drugs, all showed additive efficacy.ConclusionsThese results indicate that MXD3 is a potential new target and MXD3 siRNA nanocomplexes are a novel therapeutic approach for neuroblastoma.

show abstract

“…Precursor B-acute lymphoblastic leukaemia (pre B-ALL) is the most prevalent phenotype of ALL, and T-acute lymphoblastic leukaemia (T-ALL) associated with a poor outcome [ 3 , 4 ]. However, current standard treatment consists of combination chemotherapy that is highly toxic to growing children, both in short and long terms [ 5 – 7 ]. To avoid serious side effects in chemotherapy and improve survival rates, novel anticancer agents are needed to address the emerging problem.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of autophagy potentiates anticancer property of 20(S)-ginsenoside Rh2 by promoting mitochondria-dependent apoptosis in human acute lymphoblastic leukaemia cells

Xia

Wang

et al. 2016

Oncotarget

View full text Add to dashboard Cite

Acute lymphoblastic leukaemia (ALL) is the most prevalent childhood malignancy. Although most children with ALL are cured, there is still a group of patients for which therapy fails owing to severe toxicities and drug resistance. Ginsenoside Rh2 (GRh2), a major bioactive component isolated from Panax ginseng, has been shown to have a therapeutic effect on some tumors. However, the molecular mechanisms of cell death induced by 20(S)-GRh2 in ALL cells remains unclear. In this study, we showed that 20(S)-GRh2 inhibited the cell growth and induced mitochondria-dependent apoptosis and autophagy. But it has no cytotoxic effect on human normal blood cells. Furthermore, autophagy plays a protective role in 20(S)-GRh2-induced apoptosis in ALL cell lines and human primary ALL cells. We demonstrated that either genetic or pharmacologic inhibition of autophagy could be more effective in reducing viability and enhancing 20(S)-GRh2-induced toxicity than 20(S)-GRh2 treatment alone. In addition, inhibition of autophagy could aggravate mitochondrial ROS generation and mitochondrial damage, and then accelerate mitochondria-dependent apoptosis. Taken together, these results suggest that inhibition of autophagy can sensitize ALL cells towards 20(S)-GRh2. The appropriate inhibition of autophagy could provide a powerful strategy to increase the potency of 20(S)-GRh2 as a novel anticancer agent for ALL therapy.

show abstract

Loss of MXD3 induces apoptosis of Reh human precursor B acute lymphoblastic leukemia cells

Cited by 21 publications

References 21 publications

Novel Targeted Therapy for Precursor B-Cell Acute Lymphoblastic Leukemia: Anti-CD22 Antibody-MXD3 Antisense Oligonucleotide Conjugate

Novel Targeted Therapy for Precursor B-Cell Acute Lymphoblastic Leukemia: Anti-CD22 Antibody-MXD3 Antisense Oligonucleotide Conjugate

Novel targeted therapy for neuroblastoma: silencing the MXD3 gene using siRNA

Inhibition of autophagy potentiates anticancer property of 20(S)-ginsenoside Rh2 by promoting mitochondria-dependent apoptosis in human acute lymphoblastic leukaemia cells

Contact Info

Product

Resources

About