bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2020–12–20
ten papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Targeting of the Alox12-12-HETE in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem/Progenitor Cell Function.
  2. The impact of FLT3 mutation clearance and treatment response after gilteritinib therapy on overall survival in patients with FLT3 mutation-positive relapsed/refractory acute myeloid leukemia.
  3. Interleukin-33 Promotes Cell Survival via p38 MAPK-Mediated Interleukin-6 Gene Expression and Release in Pediatric AML.
  4. Metabolic Vulnerabilities and Epigenetic Dysregulation in Myeloproliferative Neoplasms.
  5. Stromal cells promote chemoresistance of acute myeloid leukemia cells via activation of the IL-6/STAT3/OXPHOS axis.
  6. Hyperleukocytosis predicts inferior clinical outcome in pediatric acute myeloid leukemia.
  7. Optimal dosing of cytarabine in induction and post-remission therapy of acute myeloid leukemia.
  8. Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy.
  9. Combinatorial treatment with menin and FLT3 inhibitors induces complete remission in AML models with activating FLT3 mutations.
  10. The N6-methyladenosine RNA modification in acute myeloid leukemia.
  1. Cancer Manag Res. 2020 ;12 12509-12517
    Targeting of the Alox12-12-HETE in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem/Progenitor Cell Function.
    Si Gao, Jialin Hu, Yong Li.
       Introduction: Chronic myeloid leukemia (CML) is a myeloid malignancy characterized by the oncogene BCR-ABL. CML responds well to therapy targeting BCR-ABL in the chronic phase but is resistant to treatment when it progresses to the blast phase (BP). This study attempted to address whether arachidonate 12-lipoxygenase (Alox12) confers to CML drug resistance.
    Materials and Methods: We analyzed the expression of Alox12 using Western blotting, ELISA, and RT-PCR methods. Loss of functional analysis was performed using cellular activity assays on CML and normal hematopoietic stem/progenitor cells (HSPCs).
    Results: Alox12 and 12-Hydroxyeicosatetraenoic acid (12-HETE) are overexpressed in BP-CML but not HSPCs, and that Alox12-12-HETE axis is regulated by BCR-ABL. The Alox12-12-HETE axis is required for CML. Specific Alox12 inhibitor inhibits colony formation, survival, and self-renewal capacity in BP-CML HSPCs, and to a significantly greater extent than in normal HSPCs. Of note, the Alox12 inhibitor significantly augments dasatinib's efficacy in BP-CML HSPCs. Mechanism studies show that Alox12 inhibition does not affect activities of essential signaling pathways involved in maintaining stem cell function, such as Wnt, p53, and bone morphogenetic protein (BMP). In contrast, we show that Alox12 inhibition disrupts nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis and induces oxidative stress and damage in CML HSPCs and committed cells.
    Conclusion: Alox12-12-HETE axis is a specific and critical regulator of BP-CML HSPCs functions. Pharmacological inhibition of Alox12 may be useful in BP-CML.
    Keywords:  Alox12; Bcr-Abl; chronic myeloid leukemia; resistance; stem cell
    DOI:  https://doi.org/10.2147/CMAR.S280554
  2. Cancer Med. 2020 Dec 19.
    The impact of FLT3 mutation clearance and treatment response after gilteritinib therapy on overall survival in patients with FLT3 mutation-positive relapsed/refractory acute myeloid leukemia.
    Jessica K Altman, Alexander E Perl, Jason E Hill, Matt Rosales, Erkut Bahceci, Mark J Levis.
      The FLT3 inhibitor gilteritinib has clinical activity in patients with FLT3-mutated (FLT3mut+ ) relapsed/refractory (R/R) acute myeloid leukemia (AML). The impact of FLT3 mutation clearance and the achievement of composite complete remission (CRc) and complete remission/complete remission with partial hematologic recovery (CR/CRh) on overall survival (OS) in patients with FLT3mut+ R/R AML treated with single-agent gilteritinib in a phase 1/2 trial were evaluated. Using next-generation sequencing, a FLT3-ITD variant allele frequency of ≤10-4 was used to define FLT3-ITD clearance in patients with no morphologic leukemia (ie, CRc). A total of 108 patients with FLT3-ITD-positive (FLT3-ITD+) R/R AML were analyzed; 95 of these patients had received ≥80-mg/day gilteritinib. Ten of the 95 patients had FLT3-ITD clearance; eight of these 10 patients achieved CRc and were considered negative for measurable residual disease. There was a trend toward longer OS in patients who attained CRc with FLT3-ITD clearance (131.4 weeks) versus those who achieved CRc and did not have FLT3-ITD clearance (n = 41; 43.3 weeks; HR = 0.416; p = 0.066). Among patients treated with ≥80-mg/day gilteritinib who achieved CR/CRh (n = 24), seven had FLT3-ITD clearance. Among patients who received 120-mg/day gilteritinib, those who achieved CR/CRh had a longer median OS (70.6 weeks) and higher 52-week survival probability (66.7%) than patients who did not achieve CR/CRh (n = 71; median OS, 41.7 weeks; 52-week survival probability, 20.2%). Overall, these data suggest that gilteritinib can induce deep molecular responses in patients with FLT3-ITD+ R/R AML, and in the setting of CRc or CR/CRh, these responses may be associated with prolonged survival.
    Keywords:  FLT3 inhibitor; Fms-like tyrosine kinase 3; internal tandem duplication; morphologic remission
    DOI:  https://doi.org/10.1002/cam4.3652
  3. Front Immunol. 2020 ;11 595053
    Interleukin-33 Promotes Cell Survival via p38 MAPK-Mediated Interleukin-6 Gene Expression and Release in Pediatric AML.
    Yiqian Wang, Haibo Su, Muxia Yan, Li Zhang, Jiancheng Tang, Quanxin Li, Xiaoqiong Gu, Qing Gong.
      Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of immature myeloid blasts in the bone marrow (BM). Cytokine provide signals for leukemia cells to improve their survival in the BM microenvironment. Previously, we identified interleukin-33 (IL-33) as a promoter of cell survival in a human AML cell line and primary mouse leukemia cells. In this study, we report that the cell surface expression of IL-33-specific receptor, Interleukin 1 Receptor Like 1 (IL1RL1), is elevated in BM cells from AML patients at diagnosis, and the serum level of IL-33 in AML patients is higher than that of healthy donor controls. Moreover, IL-33 levels are found to be positively associated with IL-6 levels in pediatric patients with AML. In vitro, IL-33 treatment increased IL-6 mRNA expression and protein level in BM and peripheral blood (PB) cells from AML patients. Evidence was also provided that IL-33 inhibits cell apoptosis by activating p38 mitogen-activated protein kinase (MAPK) pathway using human AML cell line and AML patient samples. Finally, we confirmed that IL-33 activated IL-6 expression in a manner that required p38 MAPK pathway using clinical AML samples. Taken together, we identified a potential mechanism of IL-33-mediated survival involving p38 MAPK in pediatric AML patients that would facilitate future drug development.
    Keywords:  acute myeloid leukemia (AML); interleukin 1 receptor Like 1 (IL1RL1); interleukin-33 (IL-33); interleukin-6 (IL-6); p38 mitogen-activated protein kinase (MAPK)
    DOI:  https://doi.org/10.3389/fimmu.2020.595053
  4. Front Immunol. 2020 ;11 604142
    Metabolic Vulnerabilities and Epigenetic Dysregulation in Myeloproliferative Neoplasms.
    Vasundhara Sharma, Kenneth L Wright, Pearlie K Epling-Burnette, Gary W Reuther.
      The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are associated with clonal myelopoiesis, elevated risk of death due to thrombotic complications, and transformation to acute myeloid leukemia (AML). JAK2 inhibitors improve the quality of life for MPN patients, but these approved therapeutics do not readily reduce the natural course of disease or antagonize the neoplastic clone. An understanding of the molecular and cellular changes requisite for MPN development and progression are needed to develop improved therapies. Recently, murine MPN models were demonstrated to exhibit metabolic vulnerabilities due to a high dependence on glucose. Neoplastic hematopoietic progenitor cells in these mice express elevated levels of glycolytic enzymes and exhibit enhanced levels of glycolysis and oxidative phosphorylation, and the disease phenotype of these MPN model mice is antagonized by glycolytic inhibition. While all MPN-driving mutations lead to aberrant JAK2 activation, these mutations often co-exist with mutations in genes that encode epigenetic regulators, including loss of function mutations known to enhance MPN progression. In this perspective we discuss how altered activity of epigenetic regulators (e.g., methylation and acetylation) in MPN-driving stem and progenitor cells may alter cellular metabolism and contribute to the MPN phenotype and progression of disease. Specific metabolic changes associated with epigenetic deregulation may identify patient populations that exhibit specific metabolic vulnerabilities that are absent in normal hematopoietic cells, and thus provide a potential basis for the development of more effective personalized therapeutic approaches.
    Keywords:  EZHZ2; HDAC11; JAK2; epigenetic; metabolism; myeloproliferative neoplasm; stem cell; therapy
    DOI:  https://doi.org/10.3389/fimmu.2020.604142
  5. Ann Transl Med. 2020 Nov;8(21): 1346
    Stromal cells promote chemoresistance of acute myeloid leukemia cells via activation of the IL-6/STAT3/OXPHOS axis.
    Diyu Hou, Bin Wang, Ruolan You, Xiaoting Wang, Jingru Liu, Weiwu Zhan, Ping Chen, Tiandi Qin, Xuehao Zhang, Huifang Huang.
       Background: Bone marrow stromal cells (BMSCs) are known to promote chemoresistance in acute myeloid leukemia (AML) cells. However, the molecular basis for BMSC-associated AML chemoresistance remains largely unexplored.
    Methods: The mitochondrial oxidative phosphorylation (OXPHOS) levels of AML cells were measured by a Seahorse XFe24 cell metabolic analyzer. The activity of total or mitochondrial signal transducer and transcription activator 3 (STAT3) in AML cells was explored by flow cytometry and Western blotting. Real-time quantitative PCR, Western blotting and enzyme-linked immunosorbent assay (ELISA) were used to analyze expression of interleukin 6 (IL-6) in the human BMSC line HS-5, and IL-6 was knocked out in HS-5 cells by CRISPR/Cas9 system.
    Results: In this study, we observed that co-culturing with BMSCs heightened OXPHOS levels in AML cells, thus promoting chemoresistance in these cells. HS-5 cell-induced upregulation of OXPHOS is dependent on the activation of STAT3, especially on that of mitochondrial serine phosphorylated STAT3 (pS-STAT3) in AML cells. The relationship among pS-STAT3, OXPHOS, and chemosensitivity of AML cells induced by BMSCs was demonstrated by the STAT3 activator and inhibitor, which upregulated and downregulated the levels of mitochondrial pS-STAT3 and OXPHOS, respectively. Intriguingly, AML cells remodeled HS-5 cells to secrete more IL-6, which augmented mitochondrial OXPHOS in AML cells and stimulated their chemoresistance. IL-6 knockout in HS-5 cells impaired the ability of these cells to activate STAT3, to increase OXPHOS, or to promote chemoresistance in AML cells.
    Conclusions: BMSCs promoted chemoresistance in AML cells via the activation of the IL-6/STAT3/OXPHOS pathway. These findings exhibit a novel mechanism of chemoresistance in AML cells in the bone marrow microenvironment from a metabolic perspective.
    Keywords:  IL-6/STAT3/OXPHOS axis; acute myeloid leukemia (AML); chemosensitivity; stromal cells
    DOI:  https://doi.org/10.21037/atm-20-3191
  6. Hematology. 2020 Dec;25(1): 507-514
    Hyperleukocytosis predicts inferior clinical outcome in pediatric acute myeloid leukemia.
    Lu-Hong Xu, Jing-Wen Wang, Yin Wang, Feng-Ying Yang.
       OBJECTIVES: Hyperleukocytosis (HL) is a laboratory abnormality commonly presented in patients with acute myeloid leukemia (AML). However, large cohort studies on the clinical significance of HL in pediatric AML are paucity. Moreover, the effect of stem cell transplantation in HL patients remains unknown.
    METHODS: The clinical profiles of 885 pediatric patients with AML were downloaded from the TARGET dataset. HL was defined as an initial peripheral WBC count of ≥ 100 ×109/L. We analyzed the prevalence, clinical profile and prognosis of HL in these patients.
    RESULTS: The frequency of HL among all the pediatric AML was 22.6%. FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) mutation and gene fusion of NUP98/NSD1 occurred with higher incidence in HL patients. Overall, HL was associated with a low induction complete remission rate, and high risk of induction death. Moreover, HL predicted a significantly inferior 5-year event-free survival (EFS) (P < 0.001) and a trend of inferior 5-year overall survival (OS) (P = 0.059). However, compared with chemotherapy, stem cell transplantation had no significant effect on the survival of HL patients in terms of 5-year leukemia-free survival (P = 0.449) or OS (P = 0.447). Multivariate analysis revealed that HL was an independent prognosis factor for EFS (Hazard ratio:1.352, P = 0.013) but not for OS (Hazard ratio:1.225, P = 0.170) in pediatric AML.
    CONCLUSION: HL might predict inferior clinical outcome in pediatric AML. SCT is an effective therapy for AML, but it may have no better effect on the survival of patients with HL, compared to chemotherapy.
    Keywords:  Acute myeloid leukemia; clinical outcome; hyperleukocytosis; pediatric patients
    DOI:  https://doi.org/10.1080/16078454.2020.1859169
  7. Leukemia. 2020 Dec 16.
    Optimal dosing of cytarabine in induction and post-remission therapy of acute myeloid leukemia.
    Roland B Walter, Frederick R Appelbaum, Elihu H Estey.
      
    DOI:  https://doi.org/10.1038/s41375-020-01110-3
  8. Signal Transduct Target Ther. 2020 Dec 18. 5(1): 288
    Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy.
    Jenna L Carter, Katie Hege, Jay Yang, Hasini A Kalpage, Yongwei Su, Holly Edwards, Maik Hüttemann, Jeffrey W Taub, Yubin Ge.
      Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little improvement in survival rates has been achieved over the past few decades. This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years. In the past 20 years, research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival. Here we review the development of novel therapeutics in targeting apoptosis, receptor tyrosine kinase (RTK) signaling, hedgehog (HH) pathway, mitochondrial function, DNA repair, and c-Myc signaling. There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells. In addition, we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways. We also describe the complexity of targeting leukemia stem cells (LSCs) as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival. This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.
    DOI:  https://doi.org/10.1038/s41392-020-00361-x
  9. Blood. 2020 Dec 17. 136(25): 2958-2963
    Combinatorial treatment with menin and FLT3 inhibitors induces complete remission in AML models with activating FLT3 mutations.
    Hongzhi Miao, EunGi Kim, Dong Chen, Trupta Purohit, Katarzyna Kempinska, James Ropa, Szymon Klossowski, Winifred Trotman, Gwenn Danet-Desnoyers, Tomasz Cierpicki, Jolanta Grembecka.
      
    DOI:  https://doi.org/10.1182/blood.2020006575
  10. Curr Opin Hematol. 2020 Dec 16. Publish Ahead of Print
    The N6-methyladenosine RNA modification in acute myeloid leukemia.
    Eliza Yankova, Demetrios Aspris, Konstantinos Tzelepis.
       PURPOSE OF REVIEW: In recent years, the N6-methyladenosine (m6A) modification of RNA has been shown to play an important role in the development of acute myeloid leukemia (AML) and the maintenance of leukemic stem cells (LSCs). In this review we summarise the recent findings in the field of epitranscriptomics related to m6A and its relevance in AML.
    RECENT FINDINGS: Recent studies have focused on the role of m6A regulators in the development of AML and their potential as translational targets. The writer Methyltransferase Like 3 and its binding partner Methyltransferase Like 14, as well as the reader YTH domain-containing family protein 2, were shown to be vital for LSC survival, and their loss has detrimental effects on AML cells. Similar observations were made with the demethylases fat mass and obesity-associated protein and AlkB homologue 5 RNA demethylase. Of importance, loss of any of these genes has little to no effect on normal hemopoietic stem cells, suggesting therapeutic potential.
    SUMMARY: The field of epitranscriptomics is still in its infancy and the importance of m6A and other RNA-modifications in AML will only come into sharper focus. The development of therapeutics targeting RNA-modifying enzymes may open up new avenues for treatment of such malignancies.
    DOI:  https://doi.org/10.1097/MOH.0000000000000636
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