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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us.
iNature Acute Promyelocytic Leukemia (APL) is the M3 subtype in acute myeloid leukemia, usually PML/RARα (P/R) encoded by the PML/RARα fusion oncogene produced by t(15;17) chromosome translocation Driven by fusion oncoprotein.
Since the 1970s, Chinese scientists Professor Zhang Tingdong, Academician Wang Zhenyi, Academician Chen Zhu, Academician Chen Saijuan and other research teams have pioneered the use of arsenic trioxide and all-trans retinoic acid to attack and degrade PML/RARα (P/R) fusion cancer protein for treatment APL has greatly improved the survival rate of patients, created a precedent for small-molecule drug targeted therapy, and established my country's international leading position in the field of APL therapy.
However, some patients with APL relapse after receiving arsenic trioxide treatment due to drug-resistant mutations in the P/R fusion gene.
In addition, some patients are originally oversensitive to arsenic trioxide and chemotherapeutics.
There is currently no effective treatment for such patients.
On May 11, 2021, the team of Professor Narenmandula of Zhejiang University School of Medicine and the team of Researcher Xu Zhihong published an online publication entitled "Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins" in the new journal Blood Cancer Discovery created by the American Cancer Society (AACR).
The research paper puts forward for the first time a new theory that hyperthermia can treat cancer by specifically degrading fusion oncoproteins, which provides new ideas for cancer treatment driven by fusion oncoproteins, and also provides a broader application prospect for hyperthermia therapy.
.The research team has long been engaged in the study of the mechanism of arsenic trioxide in the treatment of leukemia and the treatment of refractory leukemia.
In this work, the team innovatively found that mild heat shock can significantly reduce the stability of the P/R fusion protein.
More importantly, heat shock has the same effect on P/R protein resistant mutants that cannot be treated at present.
It is currently known that one of the key links in the pathogenesis of APL is: P/R fusion protein recruits histone deacetylase (HDAC) and DNA methyl transfer through abnormal interaction with nuclear receptor co-repressors (NCoRs) Enzyme (DNMT) and other epigenetic modification enzymes, thereby inhibiting cell differentiation and the expression of senescence-related genes.
The research team found that heat shock can specifically target the P/R-NCoRs complex, induce abnormal aggregation of the complex and change its solubility, thereby reducing its stability.
If the interaction between P/R and NCoRs is disrupted (such as constructing P/R mutants that do not bind to NCoRs, knocking down NCoRs protein, or pretreatment with ATRA to dissociate P/R and NCoRs), heat shock cannot induce P/R protein Stability changes have occurred, confirming that NCoRs play a key role in the process of heat shock degradation of P/R fusion proteins.
The research team further found that heat shock can enhance the binding of E3 ubiquitin ligase SIAH2 to the P/R protein, and knocking down SIAH2 significantly reduces heat shock-induced ubiquitination of the P/R-NCoRs complex, indicating that SIAH2 is involved The heat shock induces the ubiquitination of the P/R-NCoRs complex, which in turn promotes its degradation mainly through the autophagy-lysosome pathway.
The mechanism of P/R stability degradation caused by heat shock and ATO is different.
Therefore, the team used the two together and found that heat shock and ATO can synergistically reduce the stability of P/R protein both in vivo and in vitro.
On this basis, Professor Narenmandula’s team tried to treat 3 patients with relapsed and refractory APL drugs (including 1 patient with PML and P/R double mutation resistance, and 2 patients with central nervous system relapse).
The combined therapy of arsenic and arsenic has alleviated the condition to a certain extent and promoted the improvement of related treatment indicators.The clinical data of these patients strongly prove that the combination of hyperthermia and arsenic has certain therapeutic potential for APL arsenic-resistant patients who are ineffective against traditional therapies.
In addition to the P/R fusion protein, the research team also found that heat shock can down-regulate the stability of other fusion oncoproteins, such as AML1/ETO and TEL/AML1.
In summary, different from traditional chemotherapy, radiotherapy and surgical treatment, this research not only provides a non-invasive, easy-to-operate, and non-invasive new solution for relapsed and refractory APL that is currently clinically helpless, but also provides a new solution for other oncoproteins by fusion.
Driven diseases provide new research directions and treatment strategies.
Postdoctoral fellows in the research group of Professor Narenmandula, Zhejiang University School of Medicine, Yasen Maimatyiming, Wang Qianqian, and Yang Chang are the co-lead authors of the article.
Professor Narenmandula of Zhejiang University School of Medicine and researcher Xu Zhihong are the co-corresponding authors of the article.
The Journal of Blood Cancer Discovery selected this work as a focus study (Spotlight), and invited Professor Hugues de Thé, an academician of the French Academy of Sciences and an international top scholar in the field of APL, to write a commentary on the research results: PML/RARA destabilization by hyperthermia: a new model for Oncogenic fusionprotein degradation? He gave a high evaluation of the work of the research team.
He believes that the research results reported by the team and the concept proposed can be used to further study the degradation of fusion oncogenic protein induced by hyperthermia, especially because of the larger molecular weight.
Misfolded and aggregated fusion oncoprotein degradation paves the way.Reference1.
de The H, Pandolfi PP, Chen Z.
Acute Promyelocytic Leukemia: A Paradigm forOncoprotein-Targeted Cure.
Cancer Cell 2017;32(5):552-60.
2.
Nasr R,Guillemin MC, Ferhi O, Soilihi H, Peres L , Berthier C, et al.
Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation.
Nat Med 2008;14(12):1333-42.
3.
Lo-Coco F,Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al.
Retinoicacid and arsenic trioxide for acute promyelocytic leukemia.
The New Englandjournal of medicine 2013;369(2):111-21.
4.
Schapira M,Calabrese MF, Bullock AN, Crews CM.
Targeted protein degradation: expanding thetoolbox.
Nat Rev Drug Discov 2019;18(12):949-63.
5.
MaimaitiyimingY, al.
Hyperthermia selectively desatbilizes fusion oncoproteins.
Blood Cancer Discovery 2021; this issue.
6.
Jeanne M,Lallemand-Breitenbach V, Ferhi O, Koken M,Le Bras M, Duffort S, et al.
PML/RARAoxidation and arsenic binding initiate the antileukemia response of As2O3.
Cancer Cell 2010; 18(1):88-98 doi S1535-6108(10)00241-2.
7.
Downes M, Ordentlich P, Kao HY, Alvarez JG, Evans RM.
Identification of a nuclear domain with deacetylase activity.
ProcNatl Acad Sci USA 2000; 97(19):10330-5.
8.
Isakson P,Bjoras M, Boe SO, Simonsen A.
Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein.
Blood 2010;116(13):2324-31.
9.
Scortegagna M,Kim H, Li JL, Yao H, Brill LM, Han J, et al.
Fine tuning of the UPR by the ubiquitin ligases Siah1/2.
PLoS Genet 2014;10(5):e1004348.
10.
Vradii D,Zaidi SK, Lian JB, van Wijnen AJ, Stein JL, Stein GS.
Point mutation in AML1disrupts subnuclear targeting, prevents myeloid differentiation, and effects atransformation-like phenotype.
Proc Natl Acad Sci USA 2005;102(20):7174-9.
Reference message: https://bloodcancerdiscov.
aacrjournals.
org/content/early/2021/04/30/2643-3230.
BCD-20-0188https://bloodcancerdiscov.
aacrjournals.
org/ content/early/2021/05/07/2643-3230.
BCD-21-0071
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us.
iNature Acute Promyelocytic Leukemia (APL) is the M3 subtype in acute myeloid leukemia, usually PML/RARα (P/R) encoded by the PML/RARα fusion oncogene produced by t(15;17) chromosome translocation Driven by fusion oncoprotein.
Since the 1970s, Chinese scientists Professor Zhang Tingdong, Academician Wang Zhenyi, Academician Chen Zhu, Academician Chen Saijuan and other research teams have pioneered the use of arsenic trioxide and all-trans retinoic acid to attack and degrade PML/RARα (P/R) fusion cancer protein for treatment APL has greatly improved the survival rate of patients, created a precedent for small-molecule drug targeted therapy, and established my country's international leading position in the field of APL therapy.
However, some patients with APL relapse after receiving arsenic trioxide treatment due to drug-resistant mutations in the P/R fusion gene.
In addition, some patients are originally oversensitive to arsenic trioxide and chemotherapeutics.
There is currently no effective treatment for such patients.
On May 11, 2021, the team of Professor Narenmandula of Zhejiang University School of Medicine and the team of Researcher Xu Zhihong published an online publication entitled "Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins" in the new journal Blood Cancer Discovery created by the American Cancer Society (AACR).
The research paper puts forward for the first time a new theory that hyperthermia can treat cancer by specifically degrading fusion oncoproteins, which provides new ideas for cancer treatment driven by fusion oncoproteins, and also provides a broader application prospect for hyperthermia therapy.
.The research team has long been engaged in the study of the mechanism of arsenic trioxide in the treatment of leukemia and the treatment of refractory leukemia.
In this work, the team innovatively found that mild heat shock can significantly reduce the stability of the P/R fusion protein.
More importantly, heat shock has the same effect on P/R protein resistant mutants that cannot be treated at present.
It is currently known that one of the key links in the pathogenesis of APL is: P/R fusion protein recruits histone deacetylase (HDAC) and DNA methyl transfer through abnormal interaction with nuclear receptor co-repressors (NCoRs) Enzyme (DNMT) and other epigenetic modification enzymes, thereby inhibiting cell differentiation and the expression of senescence-related genes.
The research team found that heat shock can specifically target the P/R-NCoRs complex, induce abnormal aggregation of the complex and change its solubility, thereby reducing its stability.
If the interaction between P/R and NCoRs is disrupted (such as constructing P/R mutants that do not bind to NCoRs, knocking down NCoRs protein, or pretreatment with ATRA to dissociate P/R and NCoRs), heat shock cannot induce P/R protein Stability changes have occurred, confirming that NCoRs play a key role in the process of heat shock degradation of P/R fusion proteins.
The research team further found that heat shock can enhance the binding of E3 ubiquitin ligase SIAH2 to the P/R protein, and knocking down SIAH2 significantly reduces heat shock-induced ubiquitination of the P/R-NCoRs complex, indicating that SIAH2 is involved The heat shock induces the ubiquitination of the P/R-NCoRs complex, which in turn promotes its degradation mainly through the autophagy-lysosome pathway.
The mechanism of P/R stability degradation caused by heat shock and ATO is different.
Therefore, the team used the two together and found that heat shock and ATO can synergistically reduce the stability of P/R protein both in vivo and in vitro.
On this basis, Professor Narenmandula’s team tried to treat 3 patients with relapsed and refractory APL drugs (including 1 patient with PML and P/R double mutation resistance, and 2 patients with central nervous system relapse).
The combined therapy of arsenic and arsenic has alleviated the condition to a certain extent and promoted the improvement of related treatment indicators.The clinical data of these patients strongly prove that the combination of hyperthermia and arsenic has certain therapeutic potential for APL arsenic-resistant patients who are ineffective against traditional therapies.
In addition to the P/R fusion protein, the research team also found that heat shock can down-regulate the stability of other fusion oncoproteins, such as AML1/ETO and TEL/AML1.
In summary, different from traditional chemotherapy, radiotherapy and surgical treatment, this research not only provides a non-invasive, easy-to-operate, and non-invasive new solution for relapsed and refractory APL that is currently clinically helpless, but also provides a new solution for other oncoproteins by fusion.
Driven diseases provide new research directions and treatment strategies.
Postdoctoral fellows in the research group of Professor Narenmandula, Zhejiang University School of Medicine, Yasen Maimatyiming, Wang Qianqian, and Yang Chang are the co-lead authors of the article.
Professor Narenmandula of Zhejiang University School of Medicine and researcher Xu Zhihong are the co-corresponding authors of the article.
The Journal of Blood Cancer Discovery selected this work as a focus study (Spotlight), and invited Professor Hugues de Thé, an academician of the French Academy of Sciences and an international top scholar in the field of APL, to write a commentary on the research results: PML/RARA destabilization by hyperthermia: a new model for Oncogenic fusionprotein degradation? He gave a high evaluation of the work of the research team.
He believes that the research results reported by the team and the concept proposed can be used to further study the degradation of fusion oncogenic protein induced by hyperthermia, especially because of the larger molecular weight.
Misfolded and aggregated fusion oncoprotein degradation paves the way.Reference1.
de The H, Pandolfi PP, Chen Z.
Acute Promyelocytic Leukemia: A Paradigm forOncoprotein-Targeted Cure.
Cancer Cell 2017;32(5):552-60.
2.
Nasr R,Guillemin MC, Ferhi O, Soilihi H, Peres L , Berthier C, et al.
Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation.
Nat Med 2008;14(12):1333-42.
3.
Lo-Coco F,Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al.
Retinoicacid and arsenic trioxide for acute promyelocytic leukemia.
The New Englandjournal of medicine 2013;369(2):111-21.
4.
Schapira M,Calabrese MF, Bullock AN, Crews CM.
Targeted protein degradation: expanding thetoolbox.
Nat Rev Drug Discov 2019;18(12):949-63.
5.
MaimaitiyimingY, al.
Hyperthermia selectively desatbilizes fusion oncoproteins.
Blood Cancer Discovery 2021; this issue.
6.
Jeanne M,Lallemand-Breitenbach V, Ferhi O, Koken M,Le Bras M, Duffort S, et al.
PML/RARAoxidation and arsenic binding initiate the antileukemia response of As2O3.
Cancer Cell 2010; 18(1):88-98 doi S1535-6108(10)00241-2.
7.
Downes M, Ordentlich P, Kao HY, Alvarez JG, Evans RM.
Identification of a nuclear domain with deacetylase activity.
ProcNatl Acad Sci USA 2000; 97(19):10330-5.
8.
Isakson P,Bjoras M, Boe SO, Simonsen A.
Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein.
Blood 2010;116(13):2324-31.
9.
Scortegagna M,Kim H, Li JL, Yao H, Brill LM, Han J, et al.
Fine tuning of the UPR by the ubiquitin ligases Siah1/2.
PLoS Genet 2014;10(5):e1004348.
10.
Vradii D,Zaidi SK, Lian JB, van Wijnen AJ, Stein JL, Stein GS.
Point mutation in AML1disrupts subnuclear targeting, prevents myeloid differentiation, and effects atransformation-like phenotype.
Proc Natl Acad Sci USA 2005;102(20):7174-9.
Reference message: https://bloodcancerdiscov.
aacrjournals.
org/content/early/2021/04/30/2643-3230.
BCD-20-0188https://bloodcancerdiscov.
aacrjournals.
org/ content/early/2021/05/07/2643-3230.
BCD-21-0071
