bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2020–07–12
twenty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-b Signaling.
  2. Extracellular ATP and CD39 activate cAMP-mediated mitochondrial stress response to promote cytarabine resistance in acute myeloid leukemia.
  3. Pan-RAF inhibition induces apoptosis in acute myeloid leukemia cells and synergizes with BCL2 inhibition.
  4. Specific patterns of H3K79 methylation influence genetic interaction of oncogenes in AML.
  5. Venetoclax and hypomethylating agents in FLT3-mutated acute myeloid leukemia.
  6. HUWE1 cooperates with RAS activation to control leukemia cell proliferation and human hematopoietic stem cells differentiation fate.
  7. E3 ligase SCFSKP2 ubiquitinates and degrades tumor suppressor C/EBPα in acute myeloid leukemia.
  8. High Expression of the SH3TC2-DT/SH3TC2 Gene Pair Associated With FLT3 Mutation and Poor Survival in Acute Myeloid Leukemia: An Integrated TCGA Analysis.
  9. The natural alkaloid Jerantinine B has activity in acute myeloid leukemia cells through a mechanism involving c-Jun.
  10. Digital Droplet PCR is a Specific and Sensitive Tool for Detecting IDH2 Mutations in Acute Myeloid LeuKemia Patients.
  11. TRIB3 destabilizes tumor suppressor PPARα expression through ubiquitin-mediated proteasome degradation in acute myeloid leukemia.
  12. RSK inhibitor BI-D1870 inhibits acute myeloid leukemia cell proliferation by targeting mitotic exit.
  13. Mathematical modeling provides evidence for niche competition in human AML and serves as a tool to improve risk stratification.
  14. Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer.
  15. Garzon R, Savona M, Baz R, et al. A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. Blood. 2017;129(24):3165-3174.
  16. The CD70 Antibody Cusatuzumab Shows Promise in Acute Myeloid Leukemia.
  17. Mitochondrial ubiquinol oxidation is necessary for tumour growth.
  18. MDM2 inhibition: an important step forward in cancer therapy.
  19. Oxidative Stress in Cancer.
  20. Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms.
  21. Glasdegib as maintenance therapy for patients with AML and MDS patients at high risk for postallogeneic stem cell transplant relapse.
  1. Cancers (Basel). 2020 Jun 30. pii: E1737. [Epub ahead of print]12(7):
    CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-b Signaling.
    Bo-Reum Kim, Seung-Hyun Jung, A-Reum Han, Gyeongsin Park, Hee-Je Kim, Bin Yuan, Venkata Lokesh Battula, Michael Andreeff, Marina Konopleva, Yeun-Jun Chung, Byung-Sik Cho.
      Given the proven importance of the CXCL12/CXCR4 axis in the stroma-acute myeloid leukemia (AML) interactions and the rapid emergence of resistance to FLT3 inhibitors, we investigated the efficacy and safety of a novel CXCR4 inhibitor, LY2510924, in combination with FLT3 inhibitors in preclinical models of AML with FLT3-ITD mutations (FLT3-ITD-AML). Quizartinib, a potent FLT3 inhibitor, induced apoptosis in FLT3-ITD-AML, while LY2510924 blocked surface CXCR4 without inducing apoptosis. LY2510924 significantly reversed stroma-mediated resistance against quizartinib mainly through the MAPK pathway. In mice with established FLT3-ITD-AML, LY2510924 induced durable mobilization and differentiation of leukemia cells, resulting in enhanced anti-leukemia effects when combined with quizartinib, whereas transient effects were seen on non-leukemic blood cells in immune-competent mice. Sequencing of the transcriptome of the leukemic cells surviving in vivo treatment with quizartinib and LY2510924 revealed that genes related to TGF-b signaling may confer resistance against the drug combination. In co-culture experiments of FLT3-ITD-AML and stromal cells, both silencing of TGF-b in stromal cells or TGF-b-receptor kinase inhibitor enhanced apoptosis by combined treatment. Disruption of the CXCL12/CXCR4 axis in FLT3-ITD-AML by LY2510924 and its negligible effects on normal immunocytes could safely enhance the potency of quizartinib, which may be further improved by blockade of TGF-b signaling.
    Keywords:  CXCR4; FLT3-ITD; LY2510924; acute myeloid leukemia; quizartinib
    DOI:  https://doi.org/10.3390/cancers12071737
  2. Cancer Discov. 2020 Jul 08. pii: CD-19-1008. [Epub ahead of print]
    Extracellular ATP and CD39 activate cAMP-mediated mitochondrial stress response to promote cytarabine resistance in acute myeloid leukemia.
    Nesrine Aroua, Emeline Boet, Margherita Ghisi, Marie-Laure Nicolau-Travers, Estelle Saland, Ryan Gwilliam, Fabienne de Toni, Mohsen Hosseini, Pierre-Luc Mouchel, Thomas Farge, Claudie Bosc, Lucille Stuani, Marie Sabatier, Fetta Mazed, Clement Larrue, Latifa Jarrou, Sarah Gandarillas, Massimiliano Bardotti, Muriel Picard, Charlotte Syrykh, Camille Laurent, Mathilde Gotanegre, Nathalie Bonnefoy, Floriant Bellvert, Jean-Charles Portais, Nathalie Nicot, Francisco Azuaje, Tony Kaoma, Carine Joffre, Jerome Tamburini, Christian Recher, Francois Vergez, Jean-Emmanuel Sarry.
      Relapses driven by chemoresistant leukemic cell populations are the main cause of mortality for patients with acute myeloid leukemia (AML). Here, we show that the ectonucleotidase CD39 (ENTPD1) is upregulated in cytarabine (AraC)-resistant leukemic cells from both AML cell lines and patient samples in vivo and in vitro. CD39 cell surface expression and activity is increased in AML patients upon chemotherapy compared to diagnosis and enrichment in CD39-expressing blasts is a marker of adverse prognosis in the clinics. High CD39 activity promotes AraC resistance by enhancing mitochondrial activity and biogenesis through activation of a cAMP-mediated adaptive mitochondrial stress response. Finally, genetic and pharmacological inhibition of CD39 eATPase activity blocks the mitochondrial reprogramming triggered by AraC treatment and markedly enhances its cytotoxicity in AML cells in vitro and in vivo. Together, these results reveal CD39 as a new residual disease marker and a promising therapeutic target to improve chemotherapy response in AML.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-1008
  3. Leukemia. 2020 Jul 10.
    Pan-RAF inhibition induces apoptosis in acute myeloid leukemia cells and synergizes with BCL2 inhibition.
    Mahesh Tambe, Ella Karjalainen, Markus Vähä-Koskela, Daria Bulanova, Bjørn T Gjertsen, Mika Kontro, Kimmo Porkka, Caroline A Heckman, Krister Wennerberg.
      Pan-RAF inhibitors have shown promise as antitumor agents in RAS and RAF mutated solid cancers. However, the efficacy of pan-RAF inhibitors in acute myeloid leukemia (AML) has not previously been explored. In AML, the RAS-RAF-MEK-ERK (MAPK) pathway is one of the most aberrantly activated oncogenic pathways, but previous targeting of this pathway by MEK inhibitors has not proven effective in clinical trials. Here we show that pan-RAF inhibition, but not MEK inhibition, induced cell death in 29% of AML samples while being nontoxic toward healthy bone marrow cells. Mechanistically, pan-RAF inhibition downregulated MCL1 protein synthesis and induced apoptosis in cells dependent on MCL1 for their survival. Furthermore, the combination of a pan-RAF and a BCL2 inhibitor overcame resistance to either compound alone in AML cell lines, as well as synergized and induced long-term responses ex vivo in AML patient samples relapsed or refractory to azacitidine + venetoclax treatment. Together, our results indicate that pan-RAF inhibition, alone or in combination with BCL2 inhibition, is a promising treatment strategy for AML.
    DOI:  https://doi.org/10.1038/s41375-020-0972-0
  4. Blood Adv. 2020 Jul 14. 4(13): 3109-3122
    Specific patterns of H3K79 methylation influence genetic interaction of oncogenes in AML.
    Molly C Kingsley, Hongbo M Xie, Bo-Rui Chen, Simone S Riedel, Taylor Pastuer, Madelyn K Bollig, Tyler Shank, Clara Libbrecht, Sally P Stabler, Aniruddha J Deshpande, Andrew M Intlekofer, Kathrin M Bernt.
      Understanding mechanisms of cooperation between oncogenes is critical for the development of novel therapies and rational combinations. Acute myeloid leukemia (AML) cells with KMT2A-fusions and KMT2A partial tandem duplications (KMT2APTD) are known to depend on the histone methyltransferase DOT1L, which methylates histone 3 lysine 79 (H3K79). About 30% of KMT2APTD AMLs carry mutations in IDH1/2 (mIDH1/2). Previous studies showed that 2-hydroxyglutarate produced by mIDH1/2 increases H3K79 methylation, and mIDH1/2 patient samples are sensitive to DOT1L inhibition. Together, these findings suggested that stabilization or increases in H3K79 methylation associated with IDH mutations support the proliferation of leukemias dependent on this mark. However, we found that mIDH1/2 and KMT2A alterations failed to cooperate in an experimental model. Instead, mIDH1/2 and 2-hydroxyglutarate exert toxic effects, specifically on KMT2A-rearranged AML cells (fusions/partial tandem duplications). Mechanistically, we uncover an epigenetic barrier to efficient cooperation; mIDH1/2 expression is associated with high global histone 3 lysine 79 dimethylation (H3K79me2) levels, whereas global H3K79me2 is obligate low in KMT2A-rearranged AML. Increasing H3K79me2 levels, specifically in KMT2A-rearrangement leukemias, resulted in transcriptional downregulation of KMT2A target genes and impaired leukemia cell growth. Our study details a complex genetic and epigenetic interaction of 2 classes of oncogenes, IDH1/2 mutations and KMT2A rearrangements, that is unexpected based on the high percentage of IDH mutations in KMT2APTD AML. KMT2A rearrangements are associated with a trend toward lower response rates to mIDH1/2 inhibitors. The substantial adaptation that has to occur for 2 initially counteracting mutations to be tolerated within the same leukemic cell may provide at least a partial explanation for this observation.
    DOI:  https://doi.org/10.1182/bloodadvances.2020001922
  5. Am J Hematol. 2020 Jul 06.
    Venetoclax and hypomethylating agents in FLT3-mutated acute myeloid leukemia.
    Ibrahim Aldoss, Jianying Zhang, Matthew Mei, Monzr M Al Malki, Shukaib Arslan, Dat Ngo, Ahmed Aribi, Haris Ali, Karamjeet Sandhu, Amandeep Salhotra, Paul Koller, Samer Khaled, Andrew Artz, David Snyder, Ryotaro Nakamura, Stephen J Forman, Anthony A Stein, Guido Marcucci, Vinod Pullarkat.
      FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent in acute myeloid leukemia (AML), and their presence confers adverse risk. FLT3-mutated (FLT3m) AML is a challenging leukemia to manage, particularly in older and unfit patients as well as patients with relapsed/refractory (r/r) disease. We retrospectively analyzed the outcomes of 50 FLT3m AML patients (17 treatment-naïve, 33 r/r) treated with venetoclax (VEN) and hypomethylating agents (HMA). The overall CR/CRi rate with VEN-HMA was 60% (94% in treatment-naïve AML and 42% in r/r AML). Early (60-days) treatment related mortality was 2%. The r/r AML setting was an independent predictor of lower complete response (OR: 0.08; 95%CI: 0.00-0.60, p= 0.03). Cytogenetics-molecular risk, concurrent mutations, the type of FLT3 mutation (ITD vs. TKD), the ITD allelic ratio, the type of HMA, age, prior exposure to HMA and receipt of prior allogeneic transplant did not independently impact response or leukemia-free survival (LFS). Concurrent IDH mutations were associated with lower CR/CRi (p=0.01), while ASXL1 or TET2 mutations showed a non-significant association toward higher CR/CRi (p=0.07, for both). However, none of the concurrent mutations were an independent predictor for response when adjusted to AML setting. In conclusion, VEN-HMA is associated with encouraging efficacy in FLT3m AML among both newly diagnosed unfit and r/r patients. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.25929
  6. Cancer Gene Ther. 2020 Jul 10.
    HUWE1 cooperates with RAS activation to control leukemia cell proliferation and human hematopoietic stem cells differentiation fate.
    Mariana Tannús Ruckert, Annet Z Brouwers-Vos, Luis Fernando P Nagano, Jan Jacob Schuringa, Vanessa Silva Silveira.
      Acute myeloid leukemia (AML) is a poor prognosis hematopoietic malignance characterized by abnormal proliferation and differentiation of hematopoietic stem cells (HSCs). Although advances in treatment have greatly improved survival rates in young patients, in the elderly population, ~70% of patients present poor prognosis. A pan-cancer analysis on the TCGA cohort showed that AML has the second higher HUWE1 expression in tumor samples among all cancer types. In addition, pathway enrichment analysis pointed to RAS signaling cascade as one of the most important pathways associated to HUWE1 expression in this particular AML cohort. In silico analysis for biological processes enrichment also revealed that HUWE1 expression is correlated with 13 genes involved in myeloid differentiation. Therefore, to understand the role of HUWE1 in human hematopoietic stem and progenitor cells (HSPC) we constitutively expressed KRASG12V oncogene concomitantly to HUWE1 knockdown in stromal co-cultures. The results showed that, in the context of KRASG12V, HUWE1 significantly reduces cell cumulative growth and changes myeloid differentiation profile of HSPCs. Overall, these observations suggest that HUWE1 might contribute to leukemic cell proliferation and impact myeloid differentiation of human HSCs, thus providing new venues for RAS-driven leukemia targeted therapy approach.
    DOI:  https://doi.org/10.1038/s41417-020-0198-3
  7. Life Sci. 2020 Jul 02. pii: S0024-3205(20)30791-8. [Epub ahead of print] 118041
    E3 ligase SCFSKP2 ubiquitinates and degrades tumor suppressor C/EBPα in acute myeloid leukemia.
    Gatha Thacker, Mukul Mishra, Akshay Sharma, Anil Kumar Singh, Sabyasachi Sanyal, Arun Kumar Trivedi.
       AIM: Transcription factor CCAAT/Enhancer binding protein alpha (C/EBPα) is a key regulator of myeloid differentiation, granulopoiesis in particular. Although CEBPA mutations are found in more than 10% in AML, functional inhibition of C/EBPα protein is also widely observed in AML. Here, we sought to examine if SKP2, an aberrantly enhanced E3 ubiquitin ligase in primary AMLs inhibits C/EBPα stability to induce differentiation block.
    MAIN METHODS: Here we employed cell based assays such transfections, immunoblotting, co-immunoprecipitation, luciferase and gel shift assays along with differentiation assays to investigate SKP2 regulated C/EBPα protein stability in acute myeloid leukemia.
    KEY FINDINGS: Here we discovered that oncogenic E3 ubiquitin ligase SCFskp2 ubiquitinates and destabilizes C/EBPα in a proteasome-dependent manner. Our data demonstrates that SKP2 physically interacts with C-terminal of C/EBPα and promotes its K48-linked ubiquitination-mediated degradation leading to its reduced transactivation potential, DNA binding ability and cellular functions. We further show that while overexpression of SKP2 inhibits both ectopic as well as endogenous C/EBPα in heterologous (HEK293T) as well as myeloid leukemia cells respectively, SKP2 depletion restores endogenous C/EBPα leading to reduced colony formation and enhanced myeloid differentiation of myeloid leukemia cells. Using Estradiol-inducible K562-C/EBPα-ER cells as yet another model of granulocytic differentiation, we further confirmed that SKP2 overexpression indeed inhibits granulocytic differentiation by mitigating C/EBPα stability.
    SIGNIFICANCE: Our findings identify SKP2 as a potential negative regulator of C/EBPα stability and function in AML which suggests that SKP2 can be potentially targeted in AML to restore C/EBPα and overcome differentiation block.
    Keywords:  Acute myeloid leukemia; C/EBPα; Myeloid differentiation; SKP2; Ubiquitination
    DOI:  https://doi.org/10.1016/j.lfs.2020.118041
  8. Front Oncol. 2020 ;10 829
    High Expression of the SH3TC2-DT/SH3TC2 Gene Pair Associated With FLT3 Mutation and Poor Survival in Acute Myeloid Leukemia: An Integrated TCGA Analysis.
    Pengfei Yu, Haifeng Lan, Xianmin Song, Zengkai Pan.
      Fms-like tyrosine kinase 3 (FLT3) mutation is one of the most common mutations in acute myeloid leukemia (AML). However, the effect of FLT3 mutation on survival is currently still controversial and the leukemogenic mechanisms are still under further investigation. The aim of our study is to identify differentially expressed genes (DEGs) in FLT3-mutant AML and to find crucial DEGs whose expression level is related to prognosis for further analysis. By mining the TCGA-LAML dataset, 619 differentially expressed lncRNAs (DElncRNAs) and 1,428 differentially expressed mRNAs (DEmRNAs) were identified between FLT3-mutant and FLT3-wildtype samples. Through weighted gene correlation network analysis (WGCNA) and the following Cox proportional hazards regression analysis, we constructed the prognostic risk models to identify the hub DElncRNAs and DEmRNAs associated with AML prognosis. The presence of both SH3TC2 divergent transcript (SH3TC2-DT) and SH3TC2 in respective prognostic risk models promotes us to further study the significance of this gene pair in AML. SH3TC2-DT and SH3TC2 were identified to be coordinately high expressed in FLT3-mutant AML samples. High expression of this gene pair was associated with poor survival. Using logistic regression analysis, we found that high SH3TC2-DT/SH3TC2 expression was associated with FLT3 mutation, high WBC count, and intermediate cytogenetic and molecular-genetic risk. AML with SH3TC2-DT/SH3TC2 high expression showed enrichment of transcripts associated with stemness, quiescence, and leukemogenesis. Our study suggests that the SH3TC2-DT/SH3TC2 gene pair may be a possible biomarker to further optimize AML prognosis and may function in stemness or quiescence of FLT3-mutant leukemic stem cells (LSCs).
    Keywords:  FLT3 mutation; acute myeloid leukemia; divergent transcription; prognostic signature; the cancer genome atlas
    DOI:  https://doi.org/10.3389/fonc.2020.00829
  9. BMC Cancer. 2020 Jul 07. 20(1): 629
    The natural alkaloid Jerantinine B has activity in acute myeloid leukemia cells through a mechanism involving c-Jun.
    Hayaa Moeed Alhuthali, Tracey D Bradshaw, Kuan-Hon Lim, Toh-Seok Kam, Claire H Seedhouse.
       BACKGROUND: Acute myeloid leukemia (AML) is a heterogenous hematological malignancy with poor long-term survival. New drugs which improve the outcome of AML patients are urgently required. In this work, the activity and mechanism of action of the cytotoxic indole alkaloid Jerantinine B (JB), was examined in AML cells.
    METHODS: We used a combination of proliferation and apoptosis assays to assess the effect of JB on AML cell lines and patient samples, with BH3 profiling being performed to identify early effects of the drug (4 h). Phosphokinase arrays were adopted to identify potential driver proteins in the cellular response to JB, the results of which were confirmed and extended using western blotting and inhibitor assays and measuring levels of reactive oxygen species.
    RESULTS: AML cell growth was significantly impaired following JB exposure in a dose-dependent manner; potent colony inhibition of primary patient cells was also observed. An apoptotic mode of death was demonstrated using Annexin V and upregulation of apoptotic biomarkers (active caspase 3 and cleaved PARP). Using BH3 profiling, JB was shown to prime cells to apoptosis at an early time point (4 h) and phospho-kinase arrays demonstrated this to be associated with a strong upregulation and activation of both total and phosphorylated c-Jun (S63). The mechanism of c-Jun activation was probed and significant induction of reactive oxygen species (ROS) was demonstrated which resulted in an increase in the DNA damage response marker γH2AX. This was further verified by the loss of JB-induced C-Jun activation and maintenance of cell viability when using the ROS scavenger N-acetyl-L-cysteine (NAC).
    CONCLUSIONS: This work provides the first evidence of cytotoxicity of JB against AML cells and identifies ROS-induced c-Jun activation as the major mechanism of action.
    Keywords:  Acute myeloid leukemia; Jerantinine; c-Jun; reactive oxygen species
    DOI:  https://doi.org/10.1186/s12885-020-07119-2
  10. Cancers (Basel). 2020 Jun 30. pii: E1738. [Epub ahead of print]12(7):
    Digital Droplet PCR is a Specific and Sensitive Tool for Detecting IDH2 Mutations in Acute Myeloid LeuKemia Patients.
    Susanna Grassi, Francesca Guerrini, Elena Ciabatti, Riccardo Puccetti, Serena Salehzadeh, Maria Rita Metelli, Alessia Di Vita, Cristiana Domenichini, Francesco Caracciolo, Enrico Orciuolo, Matteo Pelosini, Elisa Mazzantini, Pietro Rossi, Francesco Mazziotta, Mario Petrini, Sara Galimberti.
      Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) interfere with cellular metabolism contributing to oncogenesis. Mutations of IDH2 at R140 and R172 residues are observed in 20% of acute myeloid leukemias (AML), and the availability of the IDH2 inhibitor Enasidenib made IDH2 mutational screening a clinical need. The aim of this study was to set a new quantitative polymerase chain reaction (PCR) technique, the drop-off digital droplet PCR (drop-off ddPCR), as a sensitive and accurate tool for detecting IDH2 mutations. With this technique we tested 60 AML patients. Sanger sequencing identified 8/60 (13.5%) mutated cases, while ddPCR and the amplification refractory mutation system (ARMS) PCR, used as a reference technique, identified mutations in 13/60 (21.6%) cases. When the outcome of IDH2-mutated was compared to that of wild-type patients, no significant difference in terms of quality of response, overall survival, or progression-free survival was observed. Finally, we monitored IDH2 mutations during follow-up in nine cases, finding that IDH2 can be considered a valid marker of minimal residual disease (MRD) in 2/3 of our patients. In conclusion, a rapid screening of IDH2 mutations is now a clinical need well satisfied by ddPCR, but the role of IDH2 as a marker for MRD still remains a matter of debate.
    Keywords:  AML; CPX-351; Enasidenib; IDH2; MRD; digital PCR
    DOI:  https://doi.org/10.3390/cancers12071738
  11. Life Sci. 2020 Jul 01. pii: S0024-3205(20)30771-2. [Epub ahead of print]257 118021
    TRIB3 destabilizes tumor suppressor PPARα expression through ubiquitin-mediated proteasome degradation in acute myeloid leukemia.
    Xu Luo, Liang Zhong, Lihua Yu, Ling Xiong, Wenran Dan, Jian Li, Jiao Ye, Xuan Chu, Chen Liu, Beizhong Liu.
       AIMS: Tribbles homolog 3 (TRIB3) is emerging as a multifunctional oncoprotein associated with various cellular events in different tumors. However, the regulatory mechanism of TRIB3 in acute myeloid leukemia (AML) remains unknown. This study aims to investigate the molecular mechanisms and uncover the functions of TRIB3 in AML.
    METHODS: Western blotting and quantitative real-time PCR were used to analyze the expression levels of TRIB3, peroxisome proliferator-activated receptor α (PPARα), apoptosis markers and autophagy markers in AML cells. Flow cytometry was used to assess cell apoptosis. The interaction of TRIB3 and PPARα was evaluated by immunofluorescence, coimmunoprecipitation, and in vivo ubiquitination assays.
    KEY FINDINGS: We demonstrated that downregulating TRIB3 in leukemic cells effectively induced apoptosis and autophagy by regulating the degradation of PPARα. Mechanistically, TRIB3 interacted with PPARα and contributed to its destabilization by promoting its ubiquitination. When PPARα was activated by its specific agonist clofibrate, the apoptosis and autophagy of AML cells were significantly enhanced. These results were confirmed by rescue experiments. Blocking PPARα expression using the PPARα inhibitor GW6471 reversed the functional influence of TRIB3 on AML cells.
    SIGNIFICANCE: The aim of this study is to provide evidence of the degradation of PPARα by TRIB3 via ubiquitin-dependent proteasomal degradation. This process meditates the progression of AML and prolongs the survival of leukemic cells. As a result, these data indicate that TRIB3 is a novel and promising therapeutic target for AML treatment.
    Keywords:  Acute myeloid leukemia; Apoptosis; Autophagy; Degradation; Peroxisome proliferator-activated receptor α; Proteasome; Tribbles homolog 3
    DOI:  https://doi.org/10.1016/j.lfs.2020.118021
  12. Oncotarget. 2020 Jun 23. 11(25): 2387-2403
    RSK inhibitor BI-D1870 inhibits acute myeloid leukemia cell proliferation by targeting mitotic exit.
    Hee-Don Chae, Ritika Dutta, Bruce Tiu, Fieke W Hoff, Benedetta Accordi, Valentina Serafin, Minyoung Youn, Min Huang, Nathan Sumarsono, Kara L Davis, Norman J Lacayo, Martina Pigazzi, Terzah M Horton, Steven M Kornblau, Kathleen M Sakamoto.
      The 90 kDa Ribosomal S6 Kinase (RSK) drives cell proliferation and survival in cancers, although its oncogenic mechanism has not been well characterized. Phosphorylated level of RSK (T573) was increased in acute myeloid leukemia (AML) patients and associated with poor survival. To examine the role of RSK in AML, we analyzed apoptosis and the cell cycle profile following treatment with BI-D1870, a potent inhibitor of RSK. BI-D1870 treatment increased the G2/M population and induced apoptosis in AML cell lines and patient AML cells. Characterization of mitotic phases showed that the metaphase/anaphase transition was significantly inhibited by BI-D1870. BI-D1870 treatment impeded the association of activator CDC20 with APC/C, but increased binding of inhibitor MAD2 to CDC20, preventing mitotic exit. Moreover, the inactivation of spindle assembly checkpoint or MAD2 knockdown released cells from BI-D1870-induced metaphase arrest. Therefore, we investigated whether BI-D1870 potentiates the anti-leukemic activity of vincristine by targeting mitotic exit. Combination treatment of BI-D1870 and vincristine synergistically increased mitotic arrest and apoptosis in acute leukemia cells. These data show that BI-D1870 induces apoptosis of AML cells alone and in combination with vincristine through blocking mitotic exit, providing a novel approach to overcoming vincristine resistance in AML cells.
    Keywords:  BI-D1870; RSK; acute myeloid leukemia; spindle assembly checkpoint; vincristine
    DOI:  https://doi.org/10.18632/oncotarget.27630
  13. Cancer Res. 2020 Jul 10. pii: canres.0283.2020. [Epub ahead of print]
    Mathematical modeling provides evidence for niche competition in human AML and serves as a tool to improve risk stratification.
    Thomas Stiehl, Wenwen Wang, Christoph Lutz, Anna Marciniak-Czochra.
      Acute myeloid leukemia (AML) is a stem cell-driven malignant disease. There is evidence that leukemic stem cells (LSC) interact with stem cell niches and outcompete hematopoietic stem cells (HSC). The impact of this interaction on the clinical course of the disease remains poorly understood. We developed and validated a mathematical model of stem cell competition in the human hematopoietic stem cell niche. Model simulations predicted how processes in the stem cell niche affect the speed of disease progression. Combining the mathematical model with data of individual patients, we quantified the selective pressure LSC exert on HSC and demonstrated the model's prognostic significance. A novel model-based risk-stratification approach allowed extraction of prognostic information from counts of healthy and malignant cells at the time of diagnosis. This model's feasibility was demonstrable based on a cohort of ALDH-rare AML patients and shows that the model-based risk stratification is an independent predictor of disease-free and overall survival. This proof of concept study shows how model-based interpretation of patient data can improve prognostic scoring and contribute to personalized medicine.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0283
  14. PLoS One. 2020 ;15(7): e0234103
    Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer.
    Sheelagh Frame, Chiara Saladino, Craig MacKay, Butrus Atrash, Peter Sheldrake, Edward McDonald, Paul A Clarke, Paul Workman, David Blake, Daniella Zheleva.
      Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546).
    DOI:  https://doi.org/10.1371/journal.pone.0234103
  15. Blood. 2020 Jul 09. 136(2): 259
    Garzon R, Savona M, Baz R, et al. A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. Blood. 2017;129(24):3165-3174.
      
    DOI:  https://doi.org/10.1182/blood.2020007231
  16. Cancer Discov. 2020 Jul 10.
    The CD70 Antibody Cusatuzumab Shows Promise in Acute Myeloid Leukemia.
      Cusatuzumab synergized with a hypomethylating agent in older patients with acute myeloid leukemia.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-106
  17. Nature. 2020 Jul 08.
    Mitochondrial ubiquinol oxidation is necessary for tumour growth.
    Inmaculada Martínez-Reyes, Luzivette Robles Cardona, Hyewon Kong, Karthik Vasan, Gregory S McElroy, Marie Werner, Hermon Kihshen, Colleen R Reczek, Samuel E Weinberg, Peng Gao, Elizabeth M Steinert, Raul Piseaux, G R Scott Budinger, Navdeep S Chandel.
      The mitochondrial electron transport chain (ETC) is necessary for tumour growth1-6 and its inhibition has demonstrated anti-tumour efficacy in combination with targeted therapies7-9. Furthermore, human brain and lung tumours display robust glucose oxidation by mitochondria10,11. However, it is unclear why a functional ETC is necessary for tumour growth in vivo. ETC function is coupled to the generation of ATP-that is, oxidative phosphorylation and the production of metabolites by the tricarboxylic acid (TCA) cycle. Mitochondrial complexes I and II donate electrons to ubiquinone, resulting in the generation of ubiquinol and the regeneration of the NAD+ and FAD cofactors, and complex III oxidizes ubiquinol back to ubiquinone, which also serves as an electron acceptor for dihydroorotate dehydrogenase (DHODH)-an enzyme necessary for de novo pyrimidine synthesis. Here we show impaired tumour growth in cancer cells that lack mitochondrial complex III. This phenotype was rescued by ectopic expression of Ciona intestinalis alternative oxidase (AOX)12, which also oxidizes ubiquinol to ubiquinone. Loss of mitochondrial complex I, II or DHODH diminished the tumour growth of AOX-expressing cancer cells deficient in mitochondrial complex III, which highlights the necessity of ubiquinone as an electron acceptor for tumour growth. Cancer cells that lack mitochondrial complex III but can regenerate NAD+ by expression of the NADH oxidase from Lactobacillus brevis (LbNOX)13 targeted to the mitochondria or cytosol were still unable to grow tumours. This suggests that regeneration of NAD+ is not sufficient to drive tumour growth in vivo. Collectively, our findings indicate that tumour growth requires the ETC to oxidize ubiquinol, which is essential to drive the oxidative TCA cycle and DHODH activity.
    DOI:  https://doi.org/10.1038/s41586-020-2475-6
  18. Leukemia. 2020 Jul 10.
    MDM2 inhibition: an important step forward in cancer therapy.
    Marina Konopleva, Giovanni Martinelli, Naval Daver, Cristina Papayannidis, Andrew Wei, Brian Higgins, Marion Ott, John Mascarenhas, Michael Andreeff.
      Targeting the interaction between tumor suppressor p53 and the E3 ligase MDM2 represents an attractive treatment approach for cancers with wild-type or functional TP53. Indeed, several small molecules have been developed and evaluated in various malignancies. We provide an overview of MDM2 inhibitors under preclinical and clinical investigation, with a focus on molecules with ongoing clinical trials, as indicated by ClinicalTrials.gov. Because preclinical and clinical exploration of combination strategies is underway, data supporting these combinations are also described. We identified the following molecules for inclusion in this review: RG7112 (RO5045337), idasanutlin (RG7388), AMG-232 (KRT-232), APG-115, BI-907828, CGM097, siremadlin (HDM201), and milademetan (DS-3032b). Information about each MDM2 inhibitor was collected from major congress records and PubMed using the following search terms: each molecule name, "MDM2"and "HDM2." Only congress records were limited by date (January 1, 2012-March 6, 2020). Special attention was given to available data in hematologic malignancies; however, available safety data in any indication are reported. Overall, targeting MDM2 is a promising treatment strategy, as evidenced by the increasing number of MDM2 inhibitors entering the clinic. Additional clinical investigation is needed to further elucidate the role of MDM2 inhibitors in the treatment of human cancers.
    DOI:  https://doi.org/10.1038/s41375-020-0949-z
  19. Cancer Cell. 2020 Jun 23. pii: S1535-6108(20)30274-9. [Epub ahead of print]
    Oxidative Stress in Cancer.
    John D Hayes, Albena T Dinkova-Kostova, Kenneth D Tew.
      Contingent upon concentration, reactive oxygen species (ROS) influence cancer evolution in apparently contradictory ways, either initiating/stimulating tumorigenesis and supporting transformation/proliferation of cancer cells or causing cell death. To accommodate high ROS levels, tumor cells modify sulfur-based metabolism, NADPH generation, and the activity of antioxidant transcription factors. During initiation, genetic changes enable cell survival under high ROS levels by activating antioxidant transcription factors or increasing NADPH via the pentose phosphate pathway (PPP). During progression and metastasis, tumor cells adapt to oxidative stress by increasing NADPH in various ways, including activation of AMPK, the PPP, and reductive glutamine and folate metabolism.
    Keywords:  AP-1; BACH1; FOXO; HIF-1alpha; HSF1; NADPH generation; NF-κB; NRF2; PGC-1alpha; TP53; adaptation; antioxidant; dormant cancer cell; folate metabolism; glutathione; initiation; metastasis; oxidative stress; pentose phosphate pathway; progression; reactive oxygen species; recurrent disease; redox signaling; reductive glutamine metabolism; thioredoxin; tumorigenesis
    DOI:  https://doi.org/10.1016/j.ccell.2020.06.001
  20. Blood. 2020 Jul 08. pii: blood.2020006868. [Epub ahead of print]
    Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms.
    Justin Taylor, Xiaoli Mi, Khrystyna Dilai North, Moritz Binder, Alexander Penson, Terra L Lasho, Katherine Knorr, Michael Haddadin, Bo Liu, Joseph Pangallo, Salima Benbarche, Daniel Howard Wiseman, Ayalew Tefferi, Stephanie Halene, Yang Liang, Mrinal M Patnaik, Robert K Bradley, Omar Abdel-Wahab.
      Large-scale sequencing studies of hematologic malignancies have revealed notable epistasis among high-frequency mutations. One of the most striking examples of epistasis occurs for mutations in RNA splicing factors. These lesions are amongst the most common alterations in myeloid neoplasms and generally occur in a mutually exclusive manner, a finding attributed to their synthetic lethal interactions and/or convergent effects. Curiously, however, patients with multiple concomitant splicing factor mutations have been observed, challenging our understanding of one of the most common examples of epistasis in hematologic malignancies. Here we performed bulk and single cell analyses of myeloid malignancy patients harboring >2 splicing factor mutations to understand the frequency and basis for the co-existence of these mutations. Although mutations in splicing factors were strongly mutually exclusive across 4,231 patients (q<0.001), 0.85% harbored two concomitant bona fide splicing factor mutations, ~50% of which were present in the same individual cells. However, the distribution of mutations in double mutants deviated from those in single mutants with selection against the most common alleles, SF3B1K700E and SRSF2P95H/L/R, and selection for less common alleles, such as SF3B1 non-K700E mutations, rare amino acid substitutions at SRSF2P95, and combined U2AF1S34/Q157 mutations. SF3B1 and SRSF2 alleles enriched in double mutants had reduced effects on RNA splicing and/or binding compared to the most common alleles. Moreover, dual U2AF1 mutations occurred in cis with preservation of the wild-type allele. These data highlight allele-specific differences as critical in regulating molecular effects of splicing factor mutations as well as their co-occurrences/exclusivities with one another.
    DOI:  https://doi.org/10.1182/blood.2020006868
  21. Blood Adv. 2020 Jul 14. 4(13): 3102-3108
    Glasdegib as maintenance therapy for patients with AML and MDS patients at high risk for postallogeneic stem cell transplant relapse.
    Andrew Kent, Sumithira Vasu, Derek Schatz, Natalie Monson, Steven Devine, Clayton Smith, Jonathan A Gutman, Daniel A Pollyea.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2020001991
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