Acute myeloid leukemia with a novel CPSF6‐RARG variant is sensitive to homoharringtonine and cytarabine chemotherapy

Zhang, Zhanglin; Jiang, Mei; Borthakur, Gautam; Luan, Shu-Qing; Huang, Xianbao; Tang, Guilin; Xu, Qian; Ji, Dexiang; Boyer, Andrew; Li, Fēi; Huang, Ruibin; You, M. James

doi:10.1002/ajh.25689

Cited by 19 publications

(20 citation statements)

References 12 publications

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“…The two other cases report diagnosed with CPSF6-RARG showed also resistance to induction treatment with ATRA or ATRA plus arsenic [83,147]. Very recently, sensitivity of CPSF6-RARG to homoharringtonine and chemotherapy was reported in one patient [85].…”

Section: Cpsf6-rarγ T(12;12)(q13;q15)mentioning

confidence: 90%

“…Different types of CPSF6-RARG fusion transcripts were found by whole genome sequencing or RNA-sequencing in five patients. All harbor the first four exons of CPSF6 including a RNA recognition motif (RRM) fused in frame to either 5'UTR or exon 4 of RARG [83][84][85]147]. None of the patients did not show any ATRA sensitivity.…”

Section: Cpsf6-rarγ T(12;12)(q13;q15)mentioning

confidence: 99%

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Classic and Variants APLs, as Viewed from a Therapy Response

Geoffroy

2020

Cancers

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Most acute promyelocytic leukemia (APL) are caused by PML-RARA, a translocation-driven fusion oncoprotein discovered three decades ago. Over the years, several other types of rare X-RARA fusions have been described, while recently, oncogenic fusion proteins involving other retinoic acid receptors (RARB or RARG) have been associated to very rare cases of acute promyelocytic leukemia. PML-RARA driven pathogenesis and the molecular basis for therapy response have been the focus of many studies, which have now converged into an integrated physio-pathological model. The latter is well supported by clinical and molecular studies on patients, making APL one of the rare hematological disorder cured by targeted therapies. Here we review recent data on APL-like diseases not driven by the PML-RARA fusion and discuss these in view of current understanding of “classic” APL pathogenesis and therapy response.

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Section: Cpsf6-rarγ T(12;12)(q13;q15)mentioning

confidence: 90%

Section: Cpsf6-rarγ T(12;12)(q13;q15)mentioning

confidence: 99%

Classic and Variants APLs, as Viewed from a Therapy Response

Geoffroy

2020

Cancers

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“…HHT appears to potentiate the anti-cancer effects of many known drugs. In AML, HHT produced additive or synergistic effects when combined with the anti-metabolite AraC, or the anthracycline aclarubicin [107,108] and with the methylation inhibitor decitabine [109]. It synergized with abivertinib, a new inhibitor of BTK that interferes with signaling events (phosphorylation of Btk, Akt, IKK, Flt3, STAT5) in AML cellular models to amplify leukemic cell death [110].…”

Section: Combining Ribosome Inhibition With Classical Chemotherapeutimentioning

confidence: 99%

Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

Gilles

Fréchin

Natchiar

et al. 2020

Cells

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The human 80S ribosome is the cellular nucleoprotein nanomachine in charge of protein synthesis that is profoundly affected during cancer transformation by oncogenic proteins and provides cancerous proliferating cells with proteins and therefore biomass. Indeed, cancer is associated with an increase in ribosome biogenesis and mutations in several ribosomal proteins genes are found in ribosomopathies, which are congenital diseases that display an elevated risk of cancer. Ribosomes and their biogenesis therefore represent attractive anti-cancer targets and several strategies are being developed to identify efficient and specific drugs. Homoharringtonine (HHT) is the only direct ribosome inhibitor currently used in clinics for cancer treatments, although many classical chemotherapeutic drugs also appear to impact on protein synthesis. Here we review the role of the human ribosome as a medical target in cancer, and how functional and structural analysis combined with chemical synthesis of new inhibitors can synergize. The possible existence of oncoribosomes is also discussed. The emerging idea is that targeting the human ribosome could not only allow the interference with cancer cell addiction towards protein synthesis and possibly induce their death but may also be highly valuable to decrease the levels of oncogenic proteins that display a high turnover rate (MYC, MCL1). Cryo-electron microscopy (cryo-EM) is an advanced method that allows the visualization of human ribosome complexes with factors and bound inhibitors to improve our understanding of their functioning mechanisms mode. Cryo-EM structures could greatly assist the foundation phase of a novel drug-design strategy. One goal would be to identify new specific and active molecules targeting the ribosome in cancer such as derivatives of cycloheximide, a well-known ribosome inhibitor.

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“…In contrast, after one course of standard HA regimen, the patient achieved CR and remained in CR until the last follow up; this patient’s CPSF6–RARG fusion transcript was the longest, and was generated by the fusion of exon 5 of CPSF6 and exon 1 of RARG . 10 The author of that report claimed that homoharringtonine is an effective drug for the novel subtype AML with CPSF6–RARG fusion. Nevertheless, in our case, considering the patient’s severe coagulation dysfunction and thrombocytopenia, we adopted a dose-adjusted HA regimen (Hom 2 mg d1-5, Ara - C 50 mg d1-7).…”

Section: Discussionmentioning

confidence: 99%

Acute myeloid leukemia with CPSF6–RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration

Han

Jin

Zheng

et al. 2021

Therapeutic Advances in Hematology

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Some subtypes of acute myeloid leukemia (AML) share morphologic, immunophenotypic, and clinical features of acute promyelocytic leukemia (APL), but lack a PML–RARA (promyelocytic leukemia–retinoic acid receptor alpha) fusion gene. Instead, they have the retinoic acid receptor beta (RARB) or retinoic acid receptor gamma (RARG) rearranged. Almost all of these AML subtypes exhibit resistance to all-trans retinoic acid (ATRA); undoubtedly, the prognosis is poor. Here, we present an AML patient resembling APL with a novel cleavage and polyadenylation specific factor 6 ( CPSF6) –RARG fusion, showing resistance to ATRA and poor response to chemotherapy with homoharringtonine and cytarabine. Simultaneously, the patient also had extramedullary infiltration.

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Acute myeloid leukemia with a novel CPSF6‐RARG variant is sensitive to homoharringtonine and cytarabine chemotherapy

Cited by 19 publications

References 12 publications

Classic and Variants APLs, as Viewed from a Therapy Response

Classic and Variants APLs, as Viewed from a Therapy Response

Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

Acute myeloid leukemia with CPSF6–RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration

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