bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021‒01‒24
eighteen papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London

  1. Blood Cancer Discov. 2021 Jan 01. 2(1): 32-53
      Acute myeloid leukemia (AML) is a caricature of normal hematopoiesis, driven from leukemia stem cells (LSC) that share some hematopoietic stem cell (HSC) programs including responsiveness to inflammatory signaling. Although inflammation dysregulates mature myeloid cells and influences stemness programs and lineage determination in HSC by activating stress myelopoiesis, such roles in LSC are poorly understood. Here, we show that S1PR3, a receptor for the bioactive lipid sphingosine-1-phosphate, is a central regulator which drives myeloid differentiation and activates inflammatory programs in both HSC and LSC. S1PR3-mediated inflammatory signatures varied in a continuum from primitive to mature myeloid states across AML patient cohorts, each with distinct phenotypic and clinical properties. S1PR3 was high in LSC and blasts of mature myeloid samples with linkages to chemosensitivity, while S1PR3 activation in primitive samples promoted LSC differentiation leading to eradication. Our studies open new avenues for therapeutic target identification specific for each AML subset.
    Keywords:  Acute myeloid leukemia; S1PR3; TNFα via NF-κB; hematopoietic stem cells; myeloid differentiation
  2. Nat Commun. 2021 01 18. 12(1): 422
      Drug tolerant/resistant leukemic stem cell (LSC) subpopulations may explain frequent relapses in acute myeloid leukemia (AML), suggesting that these relapse-initiating cells (RICs) persistent after chemotherapy represent bona fide targets to prevent drug resistance and relapse. We uncover that calcitonin receptor-like receptor (CALCRL) is expressed in RICs, and that the overexpression of CALCRL and/or of its ligand adrenomedullin (ADM), and not CGRP, correlates to adverse outcome in AML. CALCRL knockdown impairs leukemic growth, decreases LSC frequency, and sensitizes to cytarabine in patient-derived xenograft models. Mechanistically, the ADM-CALCRL axis drives cell cycle, DNA repair, and mitochondrial OxPHOS function of AML blasts dependent on E2F1 and BCL2. Finally, CALCRL depletion reduces LSC frequency of RICs post-chemotherapy in vivo. In summary, our data highlight a critical role of ADM-CALCRL in post-chemotherapy persistence of these cells, and disclose a promising therapeutic target to prevent relapse in AML.
  3. JCI Insight. 2021 Jan 21. pii: 141518. [Epub ahead of print]
      TAK-243 is a first-in-class inhibitor of ubiquitin-like modifier activating enzyme 1 (UBA1) that catalyzes ubiquitin activation, the first step in the ubiquitylation cascade. Based on its preclinical efficacy and tolerability, TAK-243 has been advanced to phase 1 clinical trials in advanced malignancies. Nonetheless, the determinants of TAK-243 sensitivity remain largely unknown. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in acute myeloid leukemia (AML) cells in the presence of TAK-243 to identify genes essential for TAK-243 action. We identified BEN domain-containing protein 3 (BEND3), a transcriptional repressor and a regulator of chromatin organization, as the top gene whose knockout confers resistance to TAK-243 in vitro and in vivo. Knockout of BEND3 dampened TAK-243 effects on ubiquitylation, proteotoxic stress, and DNA damage response. BEND3 knockout upregulated the ABC efflux transporter breast cancer resistance protein (BCRP; ABCG2), and reduced the intracellular levels of TAK-243. TAK-243 sensitivity correlated with BCRP expression in cancer cell lines of different origin. Moreover, chemical inhibition and genetic knockdown of BCRP sensitized intrinsically resistant high-BCRP cells to TAK-243. Thus, our data demonstrate that BEND3 regulates the expression of BCRP for which TAK-243 is a substrate. Moreover, BCRP expression could serve as a predictor of TAK-243 sensitivity.
    Keywords:  Cancer; Drug screens; Oncology; Therapeutics; Ubiquitin-proteosome system
  4. Haematologica. 2021 01 21.
      FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. Its expression in acute myeloid leukemia (AML) is associated with a poor prognosis. Due to this, the development of tyrosine kinase inhibitors (TKI) blocking FLT3-ITD became a rational therapeutic concept. This review describes key milestones in the clinical development of different FLT3-specific TKI with a particular focus on FLT3-TKI maintenance therapy in remission after allogeneic hematopoietic stem cell transplantation (HCT). Recent evidence from randomized trials using sorafenib in FLT3-ITD mutated AML provided a proof of concept that targeted post-HCT maintenance therapy could become a new treatment paradigm in AML.
  5. Ann Hematol. 2021 Jan 20.
      Core binding factor acute myeloid leukemia (CBF-AML), including cases with KIT mutation, is currently defined as a low-risk AML. However, some patients have poor response to treatment, and the prognostic significance of KIT mutation is still controversial. This study aimed to explore the prognostic significance of different KIT mutation subtypes and minimal residual disease (MRD) in CBF-AML. We retrospectively evaluated continuous patients diagnosed with CBF-AML in our center between January 2014 and April 2019. Of the 215 patients, 147 (68.4%) and 68 (31.6%) patients were RUNX1-RUNX1T1- and CBFB-MYH11 positive, respectively. KIT mutations were found in 71 (33.0%) patients; of them, 38 (53.5%) had D816/D820 mutations. After excluding 10 patients who died or were lost to follow-up within a half year, 42.0% (n = 86) of the remaining 205 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). An MRD > 0.1% at the end of two cycles of consolidation predicted relapse (P < 0.001). Multivariate analysis showed that D816 or D820 mutations and MRD > 0.1% at the end of two cycles of consolidation were independent adverse factors affecting relapse-free survival (RFS) and overall survival (OS). Allo-HSCT could improve RFS (74.4% vs. 34.6%, P < 0.001) and OS (78.1% vs. 52.3%, P = 0.002). In conclusion, high-risk CBF-AML patients must be identified before treatment. D816/D820 mutation, MRD > 0.1% at the end of two cycles of consolidation chemotherapy predicted poor survivals, and allo-HSCT can improve the survival of properly identified patients.
    Keywords:  Acute myeloid leukemia; Core binding factor; KIT mutation; Minimal residual disease; Prognosis
  6. Cancers (Basel). 2021 Jan 17. pii: E320. [Epub ahead of print]13(2):
      Over the past 50 years, few therapeutic advances have been made in treating acute myeloid leukemia (AML), an aggressive form of blood cancer, despite vast improvements in our ability to classify the disease. Emerging evidence suggests the immune system is important in controlling AML progression and in determining prognosis. Natural killer (NK) cells are important cytotoxic effector cells of the innate lymphoid cell (ILC) family that have been shown to have potent anti-leukemic functions. Recent studies are now revealing impairment or dysregulation of other ILCs in various types of cancers, including AML, which limits the effectiveness of NK cells in controlling cancer progression. NK cell development and function are inhibited in AML patients, which results in worse clinical outcomes; however, the specific roles of other ILC populations in AML are just now beginning to be unraveled. In this review, we summarize what is known about the role of ILC populations in AML.
    Keywords:  AHR; AML; ILC; NK; immunotherapy
  7. Mol Ther Methods Clin Dev. 2021 Mar 12. 20 181-190
      Intensive systemic chemotherapy is the gold standard of acute myeloid leukemia (AML) treatment and is associated with considerable off-target toxicities. Safer and targeted delivery systems are thus urgently needed. In this study, we evaluated a virus-like particle derived from the human type 3 adenovirus, called the adenoviral dodecahedron (Dd) to target AML cells. The vectorization of leukemic cells was proved very effective at nanomolar concentrations in a time- and dose-dependent manner, without vector toxicity. The internalization involved clathrin-mediated energy-dependent endocytosis and strongly correlated with the expression of αVβ3 integrin. The treatment of healthy donor peripheral blood mononuclear cells showed a preferential targeting of monocytes compared to lymphocytes and granulocytes. Similarly, monocytes but also AML blasts were the best-vectorized populations in patients while acute lymphoid leukemia blasts were less efficiently targeted. Importantly, AML leukemic stem cells (LSCs) could be addressed. Finally, Dd reached peripheral monocytes and bone marrow hematopoietic stem and progenitor cells following intravenous injection in mice, without excessive spreading in other organs. These findings reveal Dd as a promising myeloid vector especially for therapeutic purposes in AML blasts, LSCs, and progenitor cells.
    Keywords:  acute myeloid leukemia; adenoviral dodecahedron; delivery vector; leukemic stem cells; virus-like particles
  8. Exp Hematol. 2021 Jan 14. pii: S0301-472X(20)30666-4. [Epub ahead of print]
      BAALC is identified as a leukemia-associated gene and is highly expressed in CD34-positive hematopoietic stem cells. High BAALC expression is associated with poor prognosis in several types of acute myeloid leukemia. We explored binding partner proteins of BAALC by means of mass spectrometry and analyzed biological properties of BAALC-expressing leukemic cells. We found that BAALC physically interacts with DBN1, which is an actin-binding protein and promotes cell adhesion and mobility by forming cell membrane spines during cell-cell interactions. Drebrin1 downregulation impeded cell adhesion to bone marrow stromal cells, resulting in improvement of sensitivity to cytarabine. Taken together, our findings suggest that BAALC-DBN1 interaction contributes to the anchoring of BAALC-expressing cells in the bone marrow, which in turn leads to resistance to cytotoxic drugs. Therefore, the BAALC-DBN1 interaction provides us with an opportunity to overcome the chemotherapy resistance in BAALC-activated leukemia via functional blockage of these genes.
  9. Cancers (Basel). 2021 Jan 18. pii: E336. [Epub ahead of print]13(2):
      The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, n = 112) or autologous HSCT (Auto-HSCT, n = 54). D816V KIT mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant RUNX1-RUNX1T1 MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V KIT mutation and pre-transplant RUNX1-RUNX1T1 MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V KIT mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V KIT mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V KIT mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V KIT mutation and RUNX1-RUNX1T1 MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches.
    Keywords:  AML; D816V KIT mutation; RUNX1–RUNX1T1; hematopoietic stem cell transplantation; measurable residual disease
  10. J Adv Pract Oncol. 2019 Jul;10(5): 494-500
      There is no standard therapy for refractory acute myeloid leukemia (AML), but several salvage therapies are available (National Comprehensive Cancer Network [NCCN], 2018). Recently, there have been major developments in the treatment of AML focusing on the development of targeted and novel therapies. Ivosidenib is the first approved oral, targeted, small-molecule inhibitor of the isocitrate dehydrogenase 1 (IDH1) mutation seen in AML. IDH1 mutations have been associated with significantly worse outcomes in disease-free survival, relapse-free survival, and overall survival (NCCN, 2018). This article reviews the clinical trials and dose escalation studies that led to the U.S. Food & Drug Administration approval for ivosidenib in patients with relapsed or refractory AML with a susceptible IDH1 mutation. Patient counseling and monitoring, including dosing and administration, are important steps that advanced practitioners should be aware of. The mechanism of action and pharmacokinetic information for ivosidenib is discussed, as well as recommendations for drug-drug interaction management. Adverse events and monitoring parameters are addressed in detail, as well as how to interrupt and resume treatment due to adverse events.
  11. Nat Cancer. 2020 Oct;1(10): 998-1009
      Metabolic reprogramming is a key hallmark of cancer, but less is known about metabolic plasticity of the same tumor at different sites. Here, we investigated the metabolic adaptation of leukemia in two different microenvironments, the bone marrow and the central nervous system (CNS). We identified a metabolic signature of fatty-acid synthesis in CNS leukemia, highlighting Stearoyl-CoA desaturase (SCD1) as a key player. In vivo SCD1 overexpression increases CNS disease, whilst genetic or pharmacological inhibition of SCD1 decreases CNS load. Overall, we demonstrated that leukemic cells dynamically rewire metabolic pathways to suit local conditions and that targeting these adaptations can be exploited therapeutically.
    Keywords:  SCD1; acute lymphoblastic leukemia; central nervous system; fatty acid synthesis; metabolic reprogramming
  12. Leuk Lymphoma. 2021 Jan 18. 1-13
      The role of filgrastim during acute myeloid leukemia (AML) induction therapy remains controversial. At our institution, newly diagnosed AML patients from 2003 through 2019 were retrospectively evaluated. Patients were stratified on whether they received filgrastim within 5 days after early assessment bone marrow (BMBx) and divided into early GCSF group (eGCSF) and no-eGCSF group. A total of 121 patients were included. We found significantly shorter hospital stay (median 24 vs 26 days, p < .01), absolute neutrophil count recovery days (median 23 vs 25 days, p = .03), and intravenous antibiotics days (mean 18.5 vs 21.4 days, p = .01) in patients with eGCSF comparing with no-eGCSF. There was no significant difference regarding complete response rates; however, for those failed to achieve remission, eGCSF was associated with higher blast count. There was no significant difference regarding overall survival or progression-free survival. The use of eGCSF was associated with cost savings of $5199 per patient over no-eGCSF.
    Keywords:  Acute myeloid leukemia; cost-benefit analysis; filgrastim; induction therapy
  13. Hematol Transfus Cell Ther. 2021 Jan 03. pii: S2531-1379(20)31315-8. [Epub ahead of print]
      INTRODUCTION: One of the most critical complications in myelodysplastic syndromes (MDS) is the progression to acute myeloid leukemia (AML). The dynamics of clonal evolution in MDS and how acquired mutations can be used as biomarkers to track disease progression remains under investigation.OBJECTIVE AND METHOD: Herein, we investigated the frequency of common myeloid clonal mutations (FLT3, NPM1, JAK2, IDH1 and IDH2) in 88 patients with MDS and 35 AML patients with myelodysplasia-related changes, followed at a single reference center in northeastern Brazil.
    RESULTS: Overall, 9/88 (10%) of the MDS patients and 9/35 (26%) of the secondary AML patients had at least one mutation. While the JAK2 V617F mutation was the most frequent in the MDS patients, the FLT3, NPM1, IDH1 and IDH2 mutations were more frequently found in the secondary AML group. Furthermore, there was a higher frequency of FLT3, NPM1, IDH1 and IDH2 mutations in MDS patients classified as high-risk subtypes than in those of lower risk.
    CONCLUSION: Despite the limited sample size, our data suggest that mutations in FLT3, NPM1, IDH1 and IDH2 genes could be potential biomarkers to detect early disease progression in MDS.
    Keywords:  AML progression; Clonal evolution; Myelodysplastic syndrome
  14. Science. 2021 01 22. pii: eabc6663. [Epub ahead of print]371(6527):
      Dot1 (disruptor of telomeric silencing-1), the histone H3 lysine 79 (H3K79) methyltransferase, is conserved throughout evolution, and its deregulation is found in human leukemias. Here, we provide evidence that acetylation of histone H4 allosterically stimulates yeast Dot1 in a manner distinct from but coordinating with histone H2B ubiquitination (H2BUb). We further demonstrate that this stimulatory effect is specific to acetylation of lysine 16 (H4K16ac), a modification central to chromatin structure. We provide a mechanism of this histone cross-talk and show that H4K16ac and H2BUb play crucial roles in H3K79 di- and trimethylation in vitro and in vivo. These data reveal mechanisms that control H3K79 methylation and demonstrate how H4K16ac, H3K79me, and H2BUb function together to regulate gene transcription and gene silencing to ensure optimal maintenance and propagation of an epigenetic state.
  15. Leukemia. 2021 Jan 22.
      The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.
  16. Cancers (Basel). 2021 Jan 14. pii: E293. [Epub ahead of print]13(2):
      Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome that originates from the reciprocal translocation t(9;22)(q34;q11.2) and encodes for the constitutively active tyrosine kinase protein BCR-ABL1 from the Breakpoint Cluster Region (BCR) sequence and the Abelson (ABL1) gene. Despite BCR-ABL1 being one of the most studied oncogenic proteins, some molecular mechanisms remain enigmatic, and several of the proteins, acting either as positive or negative BCR-ABL1 regulators, are still unknown. The Drosophila melanogaster represents a powerful tool for genetic investigations and a promising model to study the BCR-ABL1 signaling pathway. To identify new components involved in BCR-ABL1 transforming activity, we conducted an extensive genetic screening using different Drosophila mutant strains carrying specific small deletions within the chromosomes 2 and 3 and the gmrGal4,UAS-BCR-ABL1 4M/TM3 transgenic Drosophila as the background. From the screening, we identified several putative candidate genes that may be involved either in sustaining chronic myeloid leukemia (CML) or in its progression. We also identified, for the first time, a tight connection between the BCR-ABL1 protein and Rab family members, and this correlation was also validated in CML patients. In conclusion, our data identified many genes that, by interacting with BCR-ABL1, regulate several important biological pathways and could promote disease onset and progression.
    Keywords:  BCR-ABL1; Drosophila melanogaster; Rab family; chronic myeloid leukemia; genetic screening