bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2020‒09‒13
twenty papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London


  1. Blood Adv. 2020 Sep 22. 4(18): 4267-4277
    Huls G, Chitu DA, Pabst T, Klein SK, Stussi G, Griskevicius L, Valk PJM, Cloos J, van de Loosdrecht AA, Breems D, van Lammeren-Venema D, van Zeventer I, Boersma R, Jongen-Lavrencic M, Fehr M, Hoogendoorn M, Manz MG, Söhne M, van Marwijk Kooy R, Deeren D, van der Poel MWM, Legdeur MC, Tick L, Chalandon Y, Ammatuna E, Blum S, Löwenberg B, Ossenkoppele GJ.
      The treatment of older, unfit patients with acute myeloid leukemia (AML) is challenging. Based on preclinical data of Bruton tyrosine kinase expression/phosphorylation and ibrutinib cytotoxicity in AML blasts, we conducted a randomized phase 2 multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in unfit (ie, Hematopoietic Cell Transplantation Comorbidity Index ≥3) AML patients and higher risk myelodysplasia patients (HOVON135/SAKK30/15 trial). In total, 144 eligible patients were randomly (1:1) assigned to either 10-day decitabine combined with ibrutinib (560 mg; sequentially given, starting the day after the last dose of decitabine) (n = 72) or to 10-day decitabine (n = 72). The addition of ibrutinib was well tolerated, and the number of adverse events was comparable for both arms. In the decitabine plus ibrutinib arm, 41% reached complete remission/complete remission with incomplete hematologic recovery (CR/CRi), the median overall survival (OS) was 11 months, and 2-year OS was 27%; these findings compared with 50% CR/CRi, median OS of 11.5 months, and 2-year OS of 21% for the decitabine group (not significant). Extensive molecular profiling at diagnosis revealed that patients with STAG2, IDH2, and ASXL1 mutations had significantly lower CR/CRi rates, whereas patients with mutations in TP53 had significantly higher CR/CRi rates. Furthermore, multicolor flow cytometry revealed that after 3 cycles of treatment, 28 (49%) of 57 patients with available bone marrow samples had no measurable residual disease. In this limited number of cases, measurable residual disease revealed no apparent impact on event-free survival and OS. In conclusion, the addition of ibrutinib does not improve the therapeutic efficacy of decitabine. This trial was registered at the Netherlands Trial Register (NL5751 [NTR6017]) and has EudraCT number 2015-002855-85.
    DOI:  https://doi.org/10.1182/bloodadvances.2020002846
  2. Clin Transl Sci. 2020 Sep 09.
    Buelow DR, Anderson JT, Pounds SB, Shi L, Lamba JK, Hu S, Gibson AA, Goodwin EA, Sparreboom A, Baker SD.
      Reduced expression of the uptake transporter, OCTN1 (SLC22A4), has been reported as a strong predictor of poor event-free and overall survival in multiple cohorts of patients with acute myeloid leukemia (AML) receiving the cytidine nucleoside analog, cytarabine (Ara-C). To further understand the mechanistic basis of interindividual variability in the functional expression of OCTN1 in AML, we hypothesized a mechanistic connection to DNA methylation-based epigenetic repression of SLC22A4. We found increased basal SLC22A4 methylation was associated with decreased Ara-C uptake in AML cell lines. Pre-treatment with hypomethylating agents, 5-azacytidine, or decitabine, restored SLC22A4 mRNA expression, increased cellular uptake of Ara-C, and was associated with increased cellular sensitivity to Ara-C compared with vehicle-treated cells. Additionally, lower SLC22A4 methylation status was associated with distinct clinical advantages in both adult and pediatric patients with AML. These findings suggest a regulatory mechanism is involved in the interindividual variability in response to Ara-C, and provides a basis for the integration of hypomethylating agents into Ara-C-based treatment regimens.
    DOI:  https://doi.org/10.1111/cts.12861
  3. Sci Adv. 2020 May;pii: eaaz5041. [Epub ahead of print]6(18):
    Fan Z, Devlin JR, Hogg SJ, Doyle MA, Harrison PF, Todorovski I, Cluse LA, Knight DA, Sandow JJ, Gregory G, Fox A, Beilharz TH, Kwiatkowski N, Scott NE, Vidakovic AT, Kelly GP, Svejstrup JQ, Geyer M, Gray NS, Vervoort SJ, Johnstone RW.
      The RNA polymerase II (POLII)-driven transcription cycle is tightly regulated at distinct checkpoints by cyclin-dependent kinases (CDKs) and their cognate cyclins. The molecular events underpinning transcriptional elongation, processivity, and the CDK-cyclin pair(s) involved remain poorly understood. Using CRISPR-Cas9 homology-directed repair, we generated analog-sensitive kinase variants of CDK12 and CDK13 to probe their individual and shared biological and molecular roles. Single inhibition of CDK12 or CDK13 induced transcriptional responses associated with cellular growth signaling pathways and/or DNA damage, with minimal effects on cell viability. In contrast, dual kinase inhibition potently induced cell death, which was associated with extensive genome-wide transcriptional changes including widespread use of alternative 3' polyadenylation sites. At the molecular level, dual kinase inhibition resulted in the loss of POLII CTD phosphorylation and greatly reduced POLII elongation rates and processivity. These data define substantial redundancy between CDK12 and CDK13 and identify both as fundamental regulators of global POLII processivity and transcription elongation.
    DOI:  https://doi.org/10.1126/sciadv.aaz5041
  4. Blood. 2020 Sep 10. pii: blood.2019001745. [Epub ahead of print]
    Kawabata KC, Zong H, Meydan C, Wyman S, Wouters BJ, Sugita M, Goswami S, Albert M, Yip W, Roboz GJ, Chen Z, Delwel R, Carroll MP, Mason C, Melnick A, Guzman ML.
      BCL6 is a transcription repressor and proto-oncogene that plays a crucial role in the innate and adaptive immune system and lymphoid neoplasms. However, its role in myeloid malignancies remains unclear. Here, we explored the role of BCL6 in acute myeloid leukemia (AML). BCL6 was expressed at variable and often high levels in AML cell lines and primary AML samples. AMLs with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors with the exception of those with monocytic differentiation. Gene expression profiling of AML cells treated with BCL6 inhibitor revealed induction of BCL6 repressed target genes and transcriptional programs linked to DNA damage checkpoints and downregulation of stem cell genes. Ex vivo treatment of primary AML cells with BCL6 inhibitor induced apoptosis and decreased colony forming capacity which correlated with the levels of BCL6 expression. Importantly, inhibition or knockdown of BCL6 in primary AML cells resulted in significant reduction of leukemia initiating capacity in mice, suggesting ablation of leukemia repopulating cell functionality. In contrast, BCL6 knockout or inhibition did not suppress the function of normal HSCs. Treatment with cytarabine (AraC) further induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to AraC. Treatment of AML patient derived xenografts (PDX) with BCL6 inhibitor plus Ara-C suggested enhanced anti-leukemia activity by this combination. Hence pharmacological inhibition of BCL6 might provide a novel therapeutic strategy for ablation of leukemia-repopulating cells and increased responsiveness to chemotherapy.
    DOI:  https://doi.org/10.1182/blood.2019001745
  5. Gut Microbes. 2020 Nov 09. 12(1): 1800897
    Hueso T, Ekpe K, Mayeur C, Gatse A, Joncquel-Chevallier Curt M, Gricourt G, Rodriguez C, Burdet C, Ulmann G, Neut C, Amini SE, Lepage P, Raynard B, Willekens C, Micol JB, De Botton S, Yakoub-Agha I, Gottrand F, Desseyn JL, Thomas M, Woerther PL, Seguy D.
      Induction chemotherapy (7 + 3 regimen) remains the gold standard for patients with acute myeloid leukemia (AML) but is responsible for gut damage leading to several complications such as bloodstream infection (BSI). We aimed to investigate the impact of induction chemotherapy on the intestinal barrier of patients with AML and in wild-type mice. Next, we assessed the potential benefit of strengthening the mucosal barrier in transgenic mice releasing a recombinant protein able to reinforce the mucus layer (Tg222). In patients, we observed a decrease of plasma citrulline, which is a marker of the functional enterocyte mass, of short-chain fatty acids and of fecal bacterial load, except for Escherichia coli and Enterococcus spp., which became dominant. Both the α and β-diversities of fecal microbiota decreased. In wild-type mice, citrulline levels decreased under chemotherapy along with an increase of E. coli and Enterococcus spp load associated with concomitant histologic impairment. By comparison with wild-type mice, Tg222 mice, 3 days after completing chemotherapy, had higher citrulline levels, a faster healing epithelium, and preserved α-diversity of their intestinal microbiota. This was associated with reduced bacterial translocations. Our results highlight the intestinal damage and the dysbiosis induced by the 7 + 3 regimen. As a proof of concept, our transgenic model suggests that strengthening the intestinal barrier is a promising approach to limit BSI and improve AML patients' outcome.
    Keywords:  Intestinal barrier; acute leukemia; chemotherapy; microbiota; mucus
    DOI:  https://doi.org/10.1080/19490976.2020.1800897
  6. Cancers (Basel). 2020 Sep 04. pii: E2521. [Epub ahead of print]12(9):
    Etienne G, Dulucq S, Bauduer F, Adiko D, Lifermann F, Dagada C, Lenoir C, Schmitt A, Klein E, Madene S, Fort MP, Bijou F, Moldovan M, Turcq B, Robbesyn F, Durrieu F, Versmée L, Katsahian S, Faberes C, Lascaux A, Mahon FX.
      Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2-3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2-3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2-3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.
    Keywords:  chronic myeloid leukemia; deep molecular responses; treatment-free remission; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.3390/cancers12092521
  7. Oncol Rep. 2020 Sep 09.
    Xu W, Huang Z, Gan Y, Chen R, Huang Y, Xue B, Jiang S, Yu Z, Yu K, Zhang S.
      Enhancement of autophagy serves as a promising therapeutic strategy for cancer, including acute myeloid leukemia (AML). Casein kinase 1α (CK1α), encoded by CSNK1A1, regulates Wnt/β‑catenin, p53 and other key signaling pathways, and is critically involved in tumor progression. However, the relationship and mechanism of CK1α with autophagy in AML still remain unclear. In the present study, it was found that AML patients had higher expression of CSNK1A1 mRNA than healthy donors. Furthermore, we analyzed 163 cases of AML patients in the LAML database of TCGA and found that AML patients with high CSNK1A1 had shorter overall survival than those with low or medium CSNK1A1 expression. Furthermore, we demonstrated that CK1α was a negative regulator of autophagy and apoptosis. Pharmacologic inhibition of CK1α using D4476 or CK1α knockdown via lentivirus‑mediated shRNA suppressed proliferation and the clone formation by enhancing autophagic flux and apoptosis in AML cell lines as well as in patient blast cells. Intriguingly, D4476‑induced cell death was aggravated in combination with an autophagy inhibitor, Spautin‑1, suggesting that autophagy may be a pro‑survival signaling. CK1α interacted with murine double minute 2 (MDM2) and p53, and CK1α inhibitor D4476 significantly upregulated p53 and phosphorylated 5' AMP‑activated protein kinase (AMPK), and substantially inhibited the phosphorylation of mammalian target of rapamycin (mTOR). Our findings indicate that CK1α promotes AML by suppressing p53 downstream of MDM2‑mediated autophagy and apoptosis, suggesting that targeting CK1α provides a therapeutic opportunity to treat AML.
    DOI:  https://doi.org/10.3892/or.2020.7760
  8. J R Soc Interface. 2020 Sep;17(170): 20200091
    Hoffmann H, Thiede C, Glauche I, Bornhaeuser M, Roeder I.
      Disease response and durability of remission are very heterogeneous in patients with acute myeloid leukaemia (AML). There is increasing evidence that the individual risk of early relapse can be predicted based on the initial treatment response. However, it is unclear how such a correlation is linked to functional aspects of AML progression and treatment. We suggest a mathematical model in which leukaemia-initiating cells and normal/healthy haematopoietic stem and progenitor cells reversibly change between an active state characterized by proliferation and chemosensitivity and a quiescent state, in which the cells do not divide, but are also insensitive to chemotherapy. Applying this model to 275 molecular time courses of nucleophosmin 1-mutated patients, we conclude that the differential chemosensitivity of the leukaemia-initiating cells together with the cells' intrinsic proliferative capacity is sufficient to reproduce both, early relapse as well as long-lasting remission. We can, furthermore, show that the model parameters associated with individual chemosensitivity and proliferative advantage of the leukaemic cells are closely linked to the patients' time to relapse, while a reliable prediction based on early response only is not possible based on the currently available data. Although we demonstrate with our approach, that the complete response data is sufficient to quantify the aggressiveness of the disease, further investigations are necessary to study how an intensive early sampling strategy may prospectively improve risk assessment and help to optimize individual treatments.
    Keywords:  acute myeloid leukaemia; leukaemia; mathematical modelling; measurable residual disease; relapse prediction; risk stratification
    DOI:  https://doi.org/10.1098/rsif.2020.0091
  9. Autophagy. 2020 Sep 11.
    Du W, Xu A, Huang Y, Cao J, Zhu H, Yang B, Shao X, He Q, Ying M.
      Although molecular targeted therapies have recently displayed therapeutic effects in acute myeloid leukemia (AML), limited response and acquired resistance remain common problems. Numerous studies have associated autophagy, an essential degradation process involved in the cellular response to stress, with the development and therapeutic response of cancers including AML. Thus, we review studies on the role of autophagy in AML development and summarize the linkage between autophagy and several recurrent genetic abnormalities in AML, highlighting the potential of capitalizing on autophagy modulation in targeted therapy for AML.
    Keywords:  acute myeloid leukemia; autophagy; autophagy modulator; genetic abnormalities; molecular targeted therapy
    DOI:  https://doi.org/10.1080/15548627.2020.1822628
  10. Dermatol Online J. 2020 Jul 15. pii: 13030/qt5gc4c36x. [Epub ahead of print]26(7):
    Karagounis TK, Rotemberg V, Geskin LJ, Jurcic JG, MDAuthors GN.
      Leukemia cutis (LC) is a dermatologic manifestation of leukemia. Its clinical implications for the patient and the biological mechanism behind the manifestation of LC are unknown. The oncology community is increasingly utilizing mutations to classify a number of malignancies to prognosticate outcomes and to choose targeted therapies. A single-center, retrospective analysis of dermatopathology cases with a diagnosis of leukemia cutis was performed. Patients with genetic testing using the Columbia Combined Cancer Panel (a targeted sequencing protocol of 467 genes) or Genoptix (targeted sequencing protocol of 44 genes) were identified. The frequency of the presence of genetic mutations in LC patients was compared to AML patients from the COSMIC (Catalogue of Somatic Mutations in Cancer) database. Twenty nine cases were confirmed to have leukemia cutis, 22 of which had acute myeloid leukemia (AML). Genetic testing was available in 11 patients. Twelve different mutations were observed with particular enrichment for NPM1 and FLT3-TKD. Our original hypothesis was that patients with LC would display a distinct mutation profile. Ultimately, the distribution of mutations observed in our cohort of LC patients largely reflects the mutational profile seen in AML patients in general.
  11. Nature. 2020 Sep 09.
    Yeow ZY, Lambrus BG, Marlow R, Zhan KH, Durin MA, Evans LT, Scott PM, Phan T, Park E, Ruiz LA, Moralli D, Knight EG, Badder LM, Novo D, Haider S, Green CM, Tutt ANJ, Lord CJ, Chapman JR, Holland AJ.
      Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer1,2. The success of poly-ADP ribose polymerase inhibitors in the treatment of breast cancers that are deficient in homologous recombination exemplifies the utility of synthetically lethal genetic interactions in the treatment of breast cancers that are driven by genomic instability3. Given that defects in homologous recombination are present in only a subset of breast cancers, there is a need to identify additional driver mechanisms for genomic instability and targeted strategies to exploit these defects in the treatment of cancer. Here we show that centrosome depletion induces synthetic lethality in cancer cells that contain the 17q23 amplicon, a recurrent copy number aberration that defines about 9% of all primary breast cancer tumours and is associated with high levels of genomic instability4-6. Specifically, inhibition of polo-like kinase 4 (PLK4) using small molecules leads to centrosome depletion, which triggers mitotic catastrophe in cells that exhibit amplicon-directed overexpression of TRIM37. To explain this effect, we identify TRIM37 as a negative regulator of centrosomal pericentriolar material. In 17q23-amplified cells that lack centrosomes, increased levels of TRIM37 block the formation of foci that comprise pericentriolar material-these foci are structures with a microtubule-nucleating capacity that are required for successful cell division in the absence of centrosomes. Finally, we find that the overexpression of TRIM37 causes genomic instability by delaying centrosome maturation and separation at mitotic entry, and thereby increases the frequency of mitotic errors. Collectively, these findings highlight TRIM37-dependent genomic instability as a putative driver event in 17q23-amplified breast cancer and provide a rationale for the use of centrosome-targeting therapeutic agents in treating these cancers.
    DOI:  https://doi.org/10.1038/s41586-020-2690-1
  12. Blood. 2020 Sep 08. pii: blood.2020005622. [Epub ahead of print]
    Song L, Yu B, Yang Y, Liang J, Zhang Y, Ding L, Wang T, Wan X, Yang X, Tang J, Wang S, Li B, Li Y, Feng H.
      Leukemogenesis is characterized by chromosomal rearrangements with additional molecular disruptions, yet the cooperative mechanisms are still unclear. Using whole-exome sequencing of a pair of monozygotic twins discordant for childhood acute lymphoblastic leukemia (ALL) with ETV6-RUNX1 (E/R) gene fusion successively after birth, we identified the R209C mutation of G protein subunit alpha o1 (GNAO1) as a new ALL risk loci. Moreover, GNAO1 missense mutations are only recurrent in ALL patients and are associated with E/R fusion. Ectopic expression of the GNAO1 R209C mutant increased its GTPase activity and promoted cell proliferation and cell neoplastic transformation. Combined with the E/R fusion, the GNAO1 R209C mutant promoted leukemogenesis through activating PI3K/Akt/mTOR signaling. Reciprocally, activated mTORC1 phosphorylated p300 acetyltransferase, which acetylated E/R and thereby enhanced the E/R transcriptional activity of GNAO1 R209C. Thus, our study provides clinical evidence for the functional cooperation of GNAO1 mutants and E/R fusion, suggesting GNAO1 as a potential therapeutic target in human leukemia.
    DOI:  https://doi.org/10.1182/blood.2020005622
  13. J Clin Invest. 2020 Sep 08. pii: 139682. [Epub ahead of print]
    Taylor J, Donoghue MT, Ho C, Petrova-Drus K, Al-Ahmadie HA, Funt SA, Zhang Y, Aypar U, Rao PN, Chavan SS, Haddadin M, Tamari R, Giralt S, Tallman MS, Rampal RK, Baez P, Kappagantula R, Kosuri S, Dogan A, Tickoo SK, Reuter VE, Bosl GJ, Iacobuzio-Donahue CA, Solit DB, Taylor BS, Feldman DR, Abdel-Wahab O.
      Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15-40. While most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal non-seminomatous GCTs develop an incurable hematologic malignancy and prior data intriguingly suggests a clonal relationship exists between hematologic malignancies and GCTs in these cases. To date however, the precise clonal relationship between GCTs and the diverse additional somatic malignancies arising in such individuals has not been determined. Here, we traced the clonal evolution and characterized the genetic features of each neoplasm from a cohort of fifteen patients with GCTs and associated hematologic malignancies. We discovered that GCTs and hematologic malignancies developing in such individuals evolved from a common shared precursor, nearly all of which harbored allelically imbalanced TP53 and/or RAS pathway mutations. Hematologic malignancies arising in this setting genetically resembled mediastinal GCTs rather than de novo myeloid neoplasms. Our findings argue that this scenario represents a unique clinical syndrome, distinct from de novo GCTs or hematologic malignancies, initiated by an ancestral precursor which gives rise to the parallel evolution of GCTs and blood cancers in these patients.
    Keywords:  Cancer; Genetics; Hematology; Leukemias
    DOI:  https://doi.org/10.1172/JCI139682
  14. Nature. 2019 Sep 11.
    Ledford H.
      
    Keywords:  CRISPR-Cas9 genome editing; Cancer; Drug discovery; Genetics
    DOI:  https://doi.org/10.1038/d41586-019-02701-6
  15. Ann Hematol. 2020 Sep 06.
    Shargian-Alon L, Wolach O, Rozovski U, Yahav D, Sela-Navon M, Rubinstein M, Oniashvilli N, Pasvolsky O, Raanani P, Yeshurun M.
      Sequential protocols combining salvage chemotherapy with reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (alloHCT) for high-risk acute myeloid leukemia (AML) have been studied more than a decade. Purpose of this retrospective analysis was to evaluate the anti-leukemic efficacy and toxicity of FLAG-IDA protocol (fludarabine, cytarabine, and idarubicin) followed by treosulfan-based conditioning for patients with active AML. From January 2014 to November 2019, a total of 29 active AML patients [median age, 64 years (range, 23-73)] were treated. All patients completed protocol regimen and were transplanted. Five patients (17%) had grade 3-4 toxicities; therefore, treosulfan was substituted with total body irradiation (TBI) non-myeloablative conditioning. Six (20%) patients died within 30 post-transplant days, all from infectious complications. Out of 23 evaluable patients on day 30, 22 (96%) achieved complete hematologic remission with full donor chimerism. Non-relapse mortality (NRM) rates at 1 and 3 years were 22% and 49%, respectively. Median overall survival (OS) was 12 (95% CI, 4-20) months. OS and disease-free survival were 50% and 46% at 1 year and 28% and 17% at 2 years, respectively. Age, gender, disease burden, number of previous lines, and comorbidity score did not predict survival. Sequential strategy combining FLAG-IDA and treosulfan may offer a salvage option for few selected patients with active AML; however, high NRM presents a major obstacle to treatment success. Future efforts should focus on reducing NRM by moderating regimen intensity and by better selection of patients.
    Keywords:  Allogeneic hematopoietic cell transplantation; Relapsed and refractory AML; Salvage; Sequential
    DOI:  https://doi.org/10.1007/s00277-020-04232-x
  16. Blood. 2020 Sep 10. pii: blood.2019004381. [Epub ahead of print]
    Vicente Dueñas C, Janssen S, Oldenburg M, Auer F, González Herrero I, Casado-García A, Isidro-Hernández M, Raboso-Gallego J, Westhoff P, Pandyra AA, Hein D, Gössling KL, Alonso-López D, De Las Rivas J, Bhatia S, Garcia-Criado FJ, García Cenador MB, Weber APM, Köhrer K, Hauer J, Fischer U, Sanchez-Garcia I, Borkhardt A.
      The majority of childhood leukemias are precursor B cell-acute lymphoblastic leukemias (pB-ALL) caused by a combination of prenatal genetic predispositions and oncogenic events occurring after birth. Although genetic predispositions are frequent in children (>1-5%), fewer than 1% of genetically predisposed carriers will develop pB-ALL. While infectious stimuli are believed to play a major role in leukemogenesis, the critical determinants are not well defined. Here, employing murine models of pB-ALL, we show that microbiome disturbances incurred by antibiotic treatment early in life were sufficient to induce leukemia in genetically predisposed mice even in the absence of infectious stimuli and independent of T-cells. Using V4 and full-length 16S rRNA sequencing of a series of fecal samples, we found that genetic predisposition to pB-ALL (Pax5 heterozygosity or ETV6-RUNX1 fusion) shaped a distinct gut microbiome. Machine learning accurately (96.8%) predicted genetic predisposition using 40 of 3,983 amplicon sequence variants (ASVs) as proxies for bacterial species. Transplantation of either wild type (WT) or Pax5+/- hematopoietic bone marrow cells into WT recipient mice revealed that the microbiome is shaped and determined in a donor-genotype-specific manner. Gas chromatography-mass spectrometric (GC-MS) analyses of sera from WT and Pax5+/- mice demonstrated the presence of a genotype-specific distinct metabolomic profile. Taken together, our data indicate that it is a lack of commensal microbiota rather than the presence of specific bacteria that promotes leukemia in genetically predisposed mice. Future large-scale longitudinal studies are required to determine whether targeted microbiome modification in children predisposed to pB-ALL could become a successful prevention strategy.
    DOI:  https://doi.org/10.1182/blood.2019004381
  17. Nature. 2020 Sep 09.
    Meitinger F, Ohta M, Lee KY, Watanabe S, Davis RL, Anzola JV, Kabeche R, Jenkins DA, Shiau AK, Desai A, Oegema K.
      Centrosomes catalyse the formation of microtubules needed to assemble the mitotic spindle apparatus1. Centrosomes themselves duplicate once per cell cycle, in a process that is controlled by the serine/threonine protein kinase PLK4 (refs. 2,3). When PLK4 is chemically inhibited, cell division proceeds without centrosome duplication, generating centrosome-less cells that exhibit delayed, acentrosomal spindle assembly4. Whether PLK4 inhibitors can be leveraged as a treatment for cancer is not yet clear. Here we show that acentrosomal spindle assembly following PLK4 inhibition depends on levels of the centrosomal ubiquitin ligase TRIM37. Low TRIM37 levels accelerate acentrosomal spindle assembly and improve proliferation following PLK4 inhibition, whereas high TRIM37 levels inhibit acentrosomal spindle assembly, leading to mitotic failure and cessation of proliferation. The Chr17q region containing the TRIM37 gene is frequently amplified in neuroblastoma and in breast cancer5-8, rendering these cancer types highly sensitive to PLK4 inhibition. We find that inactivating TRIM37 improves acentrosomal mitosis because TRIM37 prevents PLK4 from self-assembling into centrosome-independent condensates that serve as ectopic microtubule-organizing centres. By contrast, elevated TRIM37 expression inhibits acentrosomal spindle assembly through a distinct mechanism that involves degradation of the centrosomal component CEP192. Thus, TRIM37 is an essential determinant of mitotic vulnerability to PLK4 inhibition. Linkage of TRIM37 to prevalent cancer-associated genomic changes-including 17q gain in neuroblastoma and 17q23 amplification in breast cancer-may offer an opportunity to use PLK4 inhibition to trigger selective mitotic failure and provide new avenues to treatments for these cancers.
    DOI:  https://doi.org/10.1038/s41586-020-2710-1
  18. Clin Lymphoma Myeloma Leuk. 2020 Jun 26. pii: S2152-2650(20)30306-2. [Epub ahead of print]
    Signorelli J, Lei M, Lam J, Jalbut M, Amrein PC, Fathi AT, Hobbs G, Hock H, McAfee SL, Letourneau AR, Narayan R, Brunner A.
      BACKGROUND: Antifungal prophylaxis during induction for acute myeloid leukemia (AML) varies according to local rates of invasive fungal infections (IFIs). We evaluated fluconazole prophylaxis and no antifungal prophylaxis, as a natural interrupted time-series study to assess survival and infection complications.PATIENTS AND METHODS: We identified patients with AML ≥ 18 years old undergoing induction chemotherapy during 2 time periods: period 1, fluconazole prophylaxis from August 1, 2013 to September 30, 2015, and period 2, no prophylaxis from October 1, 2015 to December 31, 2017. The primary outcome was incidence of proven or probable IFI. Secondary outcomes included types of IFIs and 60-day overall survival (OS). IFI was defined by the 2002 European Organization for Research and Treatment of Cancer/Mycoses Study Group Consensus criteria.
    RESULTS: One hundred forty-four patients received induction chemotherapy over the 2 time periods. In the prophylaxis versus no-prophylaxis groups, the rate of proven or probable IFIs was 4 (5%) of 87 versus 12 (21%) of 57 (P = .01). The total number of proven IFIs was 3 (3%) of 87 versus 4 (7%) of 57 (P = .44), whereas probable IFIs were 1 (1%) of 87 versus 8 (14%) of 57 (P < .01). No difference was observed in fungemia. Incidence of IFIs was too low to detect resistance patterns. OS at 60 days was improved in with fluconazole prophylaxis compared with no prophylaxis (hazard ratio, 0.329; 95% confidence interval, 0.12-0.89; P = .028).
    CONCLUSION: Observed rates of proven or probable IFI were lower in the fluconazole prophylaxis group versus the no-prophylaxis group. Sixty-day OS was higher with fluconazole prophylaxis. Further study is required to evaluate how fluconazole may impart the differences in survival seen in this analysis.
    Keywords:  7+3; Antifungal agents; Fluconazole; Induction; Neutropenia
    DOI:  https://doi.org/10.1016/j.clml.2020.06.008
  19. Nature. 2020 Sep 09.
    Luongo TS, Eller JM, Lu MJ, Niere M, Raith F, Perry C, Bornstein MR, Oliphint P, Wang L, McReynolds MR, Migaud ME, Rabinowitz JD, Johnson FB, Johnsson K, Ziegler M, Cambronne XA, Baur JA.
      Mitochondria require nicotinamide adenine dinucleotide (NAD+) in order to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction. Mitochondrial NAD+ transporters have been identified in yeast and plants1,2 but their very existence is controversial in mammals3-5. Here we demonstrate that mammalian mitochondria are capable of taking up intact NAD+ and identify SLC25A51 (an essential6,7 mitochondrial protein of previously unknown function, also known as MCART1) as a mammalian mitochondrial NAD+ transporter. Loss of SLC25A51 decreases mitochondrial but not whole-cell NAD+ content, impairs mitochondrial respiration, and blocks the uptake of NAD+ into isolated mitochondria. Conversely, overexpression of SLC25A51 or a nearly identical paralog, SLC25A52, increases mitochondrial NAD+ levels and restores NAD+ uptake into yeast mitochondria lacking endogenous NAD+ transporters. Together, these findings identify SLC25A51 as the first transporter capable of importing NAD+ into mammalian mitochondria.
    DOI:  https://doi.org/10.1038/s41586-020-2741-7
  20. Bioorg Med Chem Lett. 2020 Sep 03. pii: S0960-894X(20)30643-0. [Epub ahead of print] 127532
    Zhang G, Zhang W, Shen C, Nan J, Chen M, Lai S, Zhong J, Li B, Wang T, Wang Y, Yang S, Li L.
      Herein we report the discovery of 1-(5-(tert-butyl)isoxazol-3-yl)-3- (3-fluorophenyl)urea derivatives as new FLT3 inhibitors that are able to overcome the drug resistance mutations: the secondary D835Y and F691L mutations on the basis of the internal tandem duplications (ITD) mutation of FLT3 (FLT3-ITD/D835Y and FLT3-ITD/F691L, respectively). The most potent compound corresponds to 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3- fluorophenyl)urea (4d), which showed IC50s (half maximal inhibitory concentrations) of 0.072 nM, 5.86 nM and 3.48 nM against FLT3-ITD, FLT3-ITD/F691L and FLT3-ITD/D835Y, respectively. Compound 4d also showed good selectivity for FLT3 in a kinase profiling assay. Collectively, 4d could be a good lead compound and deserves further in-depth studies.
    Keywords:  FLT3; drug-resistant mutation; secondary point mutations; small molecule inhibitor; structure-activity relationship
    DOI:  https://doi.org/10.1016/j.bmcl.2020.127532