Chemotherapy-resistant human acute myeloid leukemia (AML) cells are thought to be enriched in quiescent immature leukemic stem cells (LSC). To validate this hypothesis
, we developed a clinically ...relevant chemotherapeutic approach treating patient-derived xenografts (PDX) with cytarabine (AraC). AraC residual AML cells are enriched in neither immature, quiescent cells nor LSCs. Strikingly, AraC-resistant preexisting and persisting cells displayed high levels of reactive oxygen species, showed increased mitochondrial mass, and retained active polarized mitochondria, consistent with a high oxidative phosphorylation (OXPHOS) status. AraC residual cells exhibited increased fatty-acid oxidation, upregulated CD36 expression, and a high OXPHOS gene signature predictive for treatment response in PDX and patients with AML. High OXPHOS but not low OXPHOS human AML cell lines were chemoresistant
Targeting mitochondrial protein synthesis, electron transfer, or fatty-acid oxidation induced an energetic shift toward low OXPHOS and markedly enhanced antileukemic effects of AraC. Together, this study demonstrates that essential mitochondrial functions contribute to AraC resistance in AML and are a robust hallmark of AraC sensitivity and a promising therapeutic avenue to treat AML residual disease.
AraC-resistant AML cells exhibit metabolic features and gene signatures consistent with a high OXPHOS status. In these cells, targeting mitochondrial metabolism through the CD36-FAO-OXPHOS axis induces an energetic shift toward low OXPHOS and strongly enhanced antileukemic effects of AraC, offering a promising avenue to design new therapeutic strategies and fight AraC resistance in AML.
.
Most human blood γδ cells are cytolytic TCRVγ9Vδ2
+
lymphocytes with antitumor activity. They are currently investigated in several clinical trials of cancer immunotherapy but so far, their tumor ...infiltration has not been systematically explored across human cancers. Novel algorithms allowing the deconvolution of bulk tumor transcriptomes to find the relative proportions of infiltrating leucocytes, such as CIBERSORT, should be appropriate for this aim but in practice they fail to accurately recognize γδ T lymphocytes. Here, by implementing machine learning from microarray data, we first improved the computational identification of blood-derived TCRVγ9Vδ2
+
γδ lymphocytes and then applied this strategy to assess their abundance as tumor infiltrating lymphocytes (γδ TIL) in ∼10,000 cancer biopsies from 50 types of hematological and solid malignancies. We observed considerable inter-individual variation of TCRVγ9Vδ2
+
γδ TIL abundance both within each type and across the spectrum of cancers tested. We report their prominence in B cell-acute lymphoblastic leukemia (B-ALL), acute promyelocytic leukemia (M3-AML) and chronic myeloid leukemia (CML) as well as in inflammatory breast, prostate, esophagus, pancreas and lung carcinoma. Across all cancers, the abundance of αβ TILs and TCRVγ9Vδ2
+
γδ TILs did not correlate. αβ TIL abundance paralleled the mutational load of tumors and positively correlated with inflammation, infiltration of monocytes, macrophages and dendritic cells (DC), antigen processing and presentation, and cytolytic activity, in line with an association with a favorable outcome. In contrast, the abundance of TCRVγ9Vδ2
+
γδ TILs did not correlate with these hallmarks and was variably associated with outcome, suggesting that distinct contexts underlie TCRVγ9Vδ2
+
γδ TIL and αβ TIL mobilizations in cancer.
Chemotherapeutic drugs used in the treatment of acute myeloid leukemias (AMLs) are thought to induce cancer cell death through the generation of DNA double-strand breaks. Here, we report that one of ...their early effects is the loss of conjugation of the ubiquitin-like protein SUMO from its targets via reactive oxygen species (ROS)-dependent inhibition of the SUMO-conjugating enzymes. Desumoylation regulates the expression of specific genes, such as the proapoptotic gene DDIT3, and helps induce apoptosis in chemosensitive AMLs. In contrast, chemotherapeutics do not activate the ROS/SUMO axis in chemoresistant cells. However, pro-oxidants or inhibition of the SUMO pathway by anacardic acid restores DDIT3 expression and apoptosis in chemoresistant cell lines and patient samples, including leukemic stem cells. Finally, inhibition of the SUMO pathway decreases tumor growth in mice xenografted with AML cells. Thus, targeting the ROS/SUMO axis might constitute a therapeutic strategy for AML patients resistant to conventional chemotherapies.
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•Chemotherapeutic drugs induce ROS-dependent desumoylation in chemosensitive AML cells•Desumoylation regulates specific transcriptional programs and participates in apoptosis•The ROS/SUMO axis is not induced in chemoresistant AML cells•Inhibition of the SUMO pathway with anacardic acid can overcome chemoresistance
In this study, Bossis et al. show that treatment of acute myeloid leukemia cells with chemotherapeutic drugs induces a ROS-dependent loss of SUMO conjugation, which is involved in the activation of specific transcriptional programs and apoptosis. In addition, chemoresistance is associated with impaired activation of this ROS/SUMO axis. However, its targeting restores the death of chemoresistant AML cells and might thus be a way to overcome chemoresistance in patients
Approximately 20% of patients with acute myeloid leukemia (AML) present at diagnosis with hyperleukocytosis, which is commonly defined as a white blood cell count > 50 ×109 /L or >100 ×109 /L. ...Hyperleukocytic AML is an oncological emergency because the risk of early death is significant due to leukemic organinfiltration, leukostasis syndrome, disseminated intravascular coagulopathy and tumour lysis syndrome. Early management of these symptoms as well as rapid leukoreduction are critical in the therapeutic management.In the era of next-generation sequencing (NGS), considerable progress has been made in understanding the genetic diversity of AML. However, owing to the small proportion of hyperleukocytic patients generally included in clinical trials, the genomic landscape of hyperleukocytic AML and the prognostic impact of genetic lesions in this specific clinical context have not been described in detail except in a recent study from Taiwan which reported the frequency of mutations in a panel of 20 yeloidgenes.
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.
Acute myeloid leukemia (AML) with t(9;22) (q34.1; q11.2)/BCR::ABL1, a distinct entity within the group of AML with defining genetic abnormalities, belong to the adverse-risk group of the 2022 ELN ...classification. However, there is little data on outcome since the era of tyrosine kinase inhibitors. Among 5819 AML cases included in the DATAML registry, 20 patients with de novo BCR::ABL1
AML (0.3%) were identified. Eighteen patients treated with standard induction chemotherapy were analyzed in this study. Imatinib was added to chemotherapy in 16 patients. The female-to-male ratio was 1.25 and median age was 54 years. The t(9;22) translocation was the sole chromosomal abnormality in 12 patients. Main gene mutations detected by NGS were ASXL1, RUNX1 and NPM1. Compared with patients with myeloid blast phase of chronic myeloid leukemia (CML-BP), de novo BCR::ABL1
AML had higher WBC, fewer additional chromosomal abnormalities, lower CD36 or CD7 expression and no ABL1 mutations. Seventeen patients (94.4%) achieved complete remission (CR) or CR with incomplete hematologic recovery. Twelve patients were allografted in first remission. With a median follow-up of 6.3 years, the median OS was not reached and 2-year OS was 77% (95% CI: 50-91). Four out of five patients who were not transplanted did not relapse. Comparison of BCR::ABL1
AML, CML-BP, 2017 ELN intermediate (n = 643) and adverse-risk patients (n = 863) showed that patients with BCR::ABL1
AML had a significant better outcome than intermediate and adverse-risk patients. BCR::ABL1
AML patients treated with imatinib and intensive chemotherapy should not be included in the adverse-risk group of current AML classifications.
The treatment of older patients with newly diagnosed acute myeloid leukemia (AML) depends on their fitness. Fit patients receive an induction chemotherapy similar to that of younger patients to ...achieve complete remission (CR). In patients <60, post-remission treatment is based on repeated courses of intermediate-to high-dose cytarabine with or without allogeneic stem cell transplantation (SCT) according to relapse risk. For patients over 60, there is no consensus about such a strategy, and ELN recommendations suggest intermediate-dose cytarabine (IDAC) for 2–3 cycles in favorable-risk genetics, i.e., 20% of patients. For the remaining 80%, the value of intermediate dose compared to lower-dose cytarabine has not been demonstrated to date, so there is no recommendation in this setting. Nevertheless, IDAC is routinely used, especially in patients selected for allogeneic SCT or as a standard comparator in clinical trials. The IDAC regimen has been adapted to find a compromise between efficacy and toxicity from the results of the Cancer and Leukemia Group B (CALGB) phase 3 trial.
CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is ...considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65–79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10 −5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10 −5 were reported in 35 patients (26%, 95% confidence interval (CI) 19–34) in IsaRd versus 71 (53%, 95% CI 44–61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89–5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10 −5 and 10 −6 , and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10 −5 , the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877
Abstract
Classifications of acute myeloid leukemia (AML) patients rely on morphologic, cytogenetic, and molecular features. Here we have established a novel flow cytometry-based immunophenotypic ...stratification showing that AML blasts are blocked at specific stages of differentiation where features of normal myelopoiesis are preserved. Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO, and HLA-DR expression were identified in two independent cohorts of 2087 and 1209 AML patients. Hematopoietic stem cell/multipotent progenitor-like AMLs display low proliferation rate, inv(3) or
RUNX1
mutations, and high leukemic stem cell frequency as well as poor outcome, whereas granulocyte–monocyte progenitor-like AMLs have
CEBPA
mutations,
RUNX1-RUNX1T1
or
CBFB-MYH11
translocations, lower leukemic stem cell frequency, higher chemosensitivity, and better outcome.
NPM1
mutations correlate with most mature stages of leukemia arrest together with
TET2
or
IDH
mutations in granulocyte progenitors-like AML or with
DNMT3A
mutations in monocyte progenitors-like AML. Overall, we demonstrate that AML is arrested at specific stages of myeloid differentiation (SLA classification) that significantly correlate with AML genetic lesions, clinical presentation, stem cell properties, chemosensitivity, response to therapy, and outcome.
A patient with severe idiopathic lymphopenia and progressive multifocal leukoencephalopathy had T-cell exhaustion and high expression of immune checkpoint markers. Treatment with the PD-1 blocker ...nivolumab led to a reduced CSF JC viral load, stable clinical features, and an immune reconstitution inflammatory response on MRI.
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