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PURPOSE: Magrolimab is a first-in-class humanized monoclonal antibody against cluster of differentiation 47, an antiphagocytic signal used by cancer cells to evade phagocytosis. Azacitidine upregulates prophagocytic signals on AML cells, further increasing phagocytosis when combined with magrolimab. We report final phase Ib data for magrolimab with azacitidine in patients with untreated AML ineligible for intensive chemotherapy (ClinicalTrials.gov identifier: NCT03248479). PATIENTS AND METHODS: Patients with previously untreated AML, including TP53-mutant AML, received magrolimab intravenously as an initial dose (1 mg/kg, days 1 and 4), followed by 15 mg/kg once on day 8 and 30 mg/kg once weekly or every 2 weeks as maintenance. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and proportion with complete remission (CR). RESULTS: Eighty-seven patients were enrolled and treated; 72 (82.8%) had TP53 mutations with a median variant allele frequency of 61% (range, 9.8-98.7). Fifty-seven (79.2%) of TP53-mutant patients had European LeukemiaNet 2017 adverse-risk cytogenetics. Patients received a median of 4 (range, 1-39) cycles of treatment. The most common treatment-emergent adverse events included constipation (49.4%), nausea (49.4%), and diarrhea (48.3%). Thirty (34.5%) experienced anemia, and the median hemoglobin change from baseline to first postdose assessment was -0.9 g/dL (range, -3.6 to 2.5 g/dL). Twenty-eight (32.2%) patients achieved CR, including 23 (31.9%) patients with TP53 mutations. The median overall survival in TP53-mutant and wild-type patients were 9.8 months and 18.9 months, respectively. CONCLUSION: Magrolimab with azacitidine was relatively well tolerated with promising efficacy in patients with AML ineligible for intensive induction chemotherapy, including those with TP53 mutations, warranting further evaluation of magrolimab with azacitidine in AML. The phase III randomized ENHANCE-2 (ClinicalTrials.gov identifier: NCT04778397) and ENHANCE-3 (ClinicalTrials.gov identifier: NCT05079230) studies are recruiting frontline patients with AML.
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Azacitidina , Leucemia Mieloide Aguda , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inducción de Remisión , Leucemia Mieloide Aguda/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Approximately 5% to 15% of acute myeloid leukemia (AML) patients have TP53 gene mutations (TP53m), which are associated with very poor outcomes. Adults (≥18 years) with a new AML diagnosis were included from a nationwide, de-identified, real-world database. Patients receiving first-line therapy were divided into three cohorts: venetoclax (VEN) + hypomethylating agents (HMAs; Cohort A), intensive chemotherapy (Cohort B), or HMA without VEN (Cohort C). A total of 370 newly diagnosed AML patients with TP53m (n = 124), chromosome 17p deletion (n = 166), or both (n = 80) were included. The median age was 72 years (range, 24-84); most were male (59%) and White (69%). Baseline bone marrow (BM) blasts were ≤30%, 31%-50%, and >50% in 41%, 24%, and 29% of patients in Cohorts A, B, and C, respectively. BM remission (<5% blasts) with first-line therapy was reported in 54% of patients (115/215) overall, and 67% (38/57), 62% (68/110), and 19% (9/48) for respective cohorts (median BM remission duration: 6.3, 6.9, and 5.4 months). Median overall survival (95% CI) was 7.4 months (6.0-8.8) for Cohort A, 9.4 months (7.2-10.4) for Cohort B, and 5.9 months (4.3-7.5) for Cohort C. There were no differences in survival by treatment type after adjusting for the effects of relevant covariates (Cohort A vs. C adjusted hazard ratio [aHR] = 0.9; 95% CI, 0.7-1.3; Cohort A vs. B aHR = 1.0; 95% CI, 0.7-1.5; and Cohort C vs. B aHR = 1.1; 95% CI, 0.8-1.6). Patients with TP53m AML have dismal outcomes with current therapies, demonstrating the high unmet need for improved treatments.
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Genes p53 , Leucemia Mieloide Aguda , Adulto , Anciano , Femenino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Deleción Cromosómica , Cromosomas , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Proteína p53 Supresora de Tumor/genética , Persona de Mediana Edad , Anciano de 80 o más AñosRESUMEN
BACKGROUND: TP53 mutations, which are present in 5% to 10% of patients with acute myeloid leukemia (AML), are associated with treatment resistance and poor outcomes. First-line therapies for TP53-mutated (TP53m) AML consist of intensive chemotherapy (IC), hypomethylating agents (HMA), or venetoclax combined with HMA (VEN + HMA). METHODS: We conducted a systematic review and meta-analysis to describe and compare treatment outcomes in newly diagnosed treatment-naïve patients with TP53m AML. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies were included that reported on complete remission (CR), CR with incomplete hematologic recovery (CRi), overall survival (OS), event-free survival (EFS), duration of response (DoR), and overall response rate (ORR) among patients with TP53m AML receiving first-line treatment with IC, HMA, or VEN + HMA. RESULTS: Searches of EMBASE and MEDLINE identified 3006 abstracts, and 17 publications describing 12 studies met the inclusion criteria. Random-effects models were used to pool response rates, and time-related outcomes were analyzed with the median of medians method. IC was associated with the greatest CR rate of 43%, and CR rates were 33% for VEN + HMA and 13% for HMA. Rates of CR/CRi were comparable for IC (46%) and VEN + HMA (49%) but were lower for HMA (13%). Median OS was uniformly poor across treatments: IC, 6.5 months; VEN + HMA, 6.2 months; and HMA, 6.1 months. For IC, the EFS estimate was 3.7 months; EFS was not reported for VEN + HMA or HMA. The ORR was 41% for IC, 65% for VEN + HMA, and 47% for HMA. DoR was 3.5 months for IC, 5.0 months for VEN + HMA, and was not reported for HMA. CONCLUSIONS: Despite improved responses seen with IC and VEN + HMA compared to HMA, survival was uniformly poor, and clinical benefits were limited across all treatments for patients with newly diagnosed, treatment-naïve TP53m AML, demonstrating a significant need for improved treatment for this difficult-to-treat population.
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Leucemia Mieloide Aguda , Humanos , Estudios Retrospectivos , Resultado del Tratamiento , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Supervivencia sin Progresión , Mutación , Proteína p53 Supresora de Tumor/genética , Estudios Observacionales como AsuntoRESUMEN
PURPOSE: Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine (ClinicalTrials.gov identifier: NCT03248479). PATIENTS AND METHODS: Patients with previously untreated Revised International Prognostic Scoring System intermediate-/high-/very high-risk MDS received magrolimab intravenously as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg once-weekly or once-every-2-week maintenance dose. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and complete remission (CR) rate. RESULTS: Ninety-five patients were treated. Revised International Prognostic Scoring System risk was intermediate/high/very high in 27%, 52%, and 21%, respectively. Fifty-nine (62%) had poor-risk cytogenetics and 25 (26%) had TP53 mutation. The most common treatment-emergent adverse effects included constipation (68%), thrombocytopenia (55%), and anemia (52%). Median hemoglobin change from baseline to first postdose assessment was -0.7 g/dL (range, -3.1 to +2.4). CR rate and overall response rate were 33% and 75%, respectively. Median time to response, duration of CR, duration of overall response, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. Median overall survival (OS) was not reached with 17.1-month follow-up. In TP53-mutant patients, 40% achieved CR with median OS of 16.3 months. Thirty-four patients (36%) had allogeneic stem-cell transplant with 77% 2-year OS. CONCLUSION: Magrolimab + azacitidine was well tolerated with promising efficacy in patients with untreated higher-risk MDS, including those with TP53 mutations. A phase III trial of magrolimab/placebo + azacitidine is ongoing (ClinicalTrials.gov identifier: NCT04313881 [ENHANCE]).
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Azacitidina , Síndromes Mielodisplásicos/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Supervivencia sin Progresión , Leucemia Mieloide Aguda/tratamiento farmacológico , Resultado del TratamientoRESUMEN
In the version of this article originally published, the color key in Fig. 1a was wrong. In the Cytogenetics key, the box over t(8;21) originally was green. It should have been red, matching the color of the sections of the pie graphs below the key that were labeled with 15% and 19%.
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Over half of the human genome is comprised of transposable elements (TE). Despite large-scale studies of the transcriptome in cancer, a comprehensive look at TE expression and its relationship to various mutations or prognosis has not been performed. We characterized the expression of TE in 178 adult acute myeloid leukemia (AML) patients using transcriptome data from The Cancer Genome Atlas. We characterized mutation specific dysregulation of TE expression using a multivariate linear model. We identified distinct patterns of TE expression associated with specific mutations and transcriptional networks. Genes regulating methylation was not associated with significant change in TE expression. Using an unpenalized cox regression analysis we identified a TE expression signature that predicted prognosis in AML. We identified 14 candidate prognostic TE transcripts (TEP) that classified AML as high/low-risk and this was independent of mutation-based and coding-gene expression based risk-stratification. TEP was able to predict prognosis in independent cohorts of 284 pediatric AML patients and 19 relapsed adult AML patients. This first comprehensive study of TE expression in AML demonstrates that TE expression can serve as a biomarker for prognosis in AML, and provides novel insights into the biology of AML. Studies characterizing its role in other cancers are warranted.
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Elementos Transponibles de ADN , Regulación Neoplásica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Mutación , Transcriptoma , Adulto , Perfilación de la Expresión Génica , Humanos , PronósticoRESUMEN
Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal disease primarily of children, characterized by a severe hyperinflammatory state. We describe a case of adult onset familial HLH with a novel exon 19, c.1607G>T (p.Arg536Leu) heterozygous mutation of the UNC13D gene in a 40-year-old woman who developed HLH during her first and second pregnancies, both episodes occurring during the first trimester. Our patient was treated successfully both times with HLH-94 protocol following spontaneous abortions and is currently in the process of getting a bone marrow transplant. We also discuss pregnancy as a potential trigger for late onset familial HLH.
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Senescent cells constitutively secrete inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). Previous work has implicated SASP in immune-mediated clearance of senescent cells; however, its regulation remains unknown. Our recent transcriptome profiling study has shown that human senescent human stem and progenitors (s-HSPCs) robustly express genomic transposable elements (TEs) and pathways of inflammation. Furthermore, hypomethylating agents have been previously shown to induce expression of TEs and activate the dsRNA recognition pathway and downstream interferon-stimulated genes, leading to immune mediated cell death. Therefore, to examine whether activation of TEs occurred universally, independent of their modality of senescence induction, we performed transcriptomic analysis in artificially-induced senescent cell-lines and observed a robust activation of TEs. Hence we propose that the expression of TEs might play a role in immune mediated clearance of senescent cells.
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Senescencia Celular/genética , Elementos Transponibles de ADN/genética , Azacitidina/farmacología , Senescencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Virus/metabolismoRESUMEN
Activating mutations in FLT3 in acute myeloid leukemia (AML) portend a poor prognosis, and targeting FLT3 with a tyrosine kinase inhibitor has been an area of intense research recently. Most FLT3 mutated AML patients undergo hematopoietic stem cell transplantation (HSCT) as standard of care but a significant proportion of patients relapse. Although the use of FLT3 inhibitors in the pre-HSCT perspective is more clearly defined, its use in the post-HSCT scenario, when most relapses occur, remains unclear. In this review, we comprehensively present the data on the recent and ongoing studies evaluating the role of various FLT3 inhibitors in AML with a particular focus in the post-HSCT setting.
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BACKGROUND: Aging is associated with complex molecular alterations at the cellular level. Bone marrow exhibits distinct phenotypic, genetic and epigenetic alterations with aging. Metabolic changes in the bone marrow related to aging have not been studied. METHODS: In this study, we characterized the metabolome and transcriptome of aging murine bone marrow and compared it with bone marrow from young healthy mice and chemotherapy treated mice; chemotherapy treatment is known to induce age-related changes in hematopoiesis. RESULTS: The metabolome of the aging bone marrow exhibited a signature of suppressed fatty-acid oxidation: accumulation of free fatty acids, reduced acyl-carnitines and low ß-hydroxy butyric acid. The aged bone marrow also exhibited a significant reduction in amino acid and nucleic acid pool. The transcriptome of the aging bone marrow revealed a signature of oxidative stress, known to be associated with mitochondrial dysfunction. Lastly, the metabolic and transcriptomic profiles of the bone marrow of chemotherapy treated mice did not show broad age-related changes but rather mostly resembled young healthy mice, suggestive of a lack of 'metabolic aging' with chemotherapy exposure. CONCLUSION: Our results revealed broad changes in lipids, amino acids, and nucleotides in aging marrow tissue. Together, these data provide a rich resource for the study of metabolic changes associated with aging in bone marrow.
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This corrects the article DOI: 10.1038/nm.4439.
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A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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Microtransplantation (MST), a type of HLA-mismatched allogeneic cellular therapy, is a promising, cellular therapy for acute myeloid leukemia (AML). MST transfuses granulocyte colony-stimulating factor (G-CSF)-mobilized, HLA-mismatched donor peripheral blood stem cells into patients undergoing conventional chemotherapy. MST, using haploidentical donors, has been shown to yield clinical benefit without any permanent marrow engraftment in AML. Consequently, graft-versus-host disease concerns are rendered irrelevant with no need for immunosuppression. We describe the first reported patient with refractory AML who underwent salvage MST from an unrelated, complete HLA-mismatched donor. The patient achieved remission without complication, warranting further study of unrelated HLA-mismatched donor MST in AML.
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Genomic transposable elements (TEs) constitute the majority of the genome. Expression of TEs is known to activate the double-stranded RNA recognition pathway ("viral mimicry"), leading to the activation of interferon-stimulated genes, inflammation, and immune-mediated cell death. Recently, we showed that the expression of TEs is suppressed along with immune pathways in leukemic stem cells (LSCs) in acute myeloid leukemia, suggesting a potential mechanism for immune escape of LSCs. This indicated that, during oncogenesis, where there is escape from senescence, expression of TEs is suppressed. Senescence is known to activate the interferon response and inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). We characterized the transcriptome of senescent and active human hematopoietic stem and progenitor cells (HSPCs) in vivo and showed co-occurrence of overexpression of TEs, SASP genes, and gene pathways of inflammation in senescence. The percentage of circulating senescent HSPCs (s-HSPCs) did not increase with age, indicating active clearance. Induction of senescence in human HSPCs in vitro showed increased expression of TE and SASP genes. SASP is known to mediate clearance of senescent cells and active clearance of senescent cells has been shown to increase organismal fitness. We speculate that the expression of TEs in s-HSPCs could contribute to orderly clearance of the cells via activation of immune pathways, warranting further mechanistic studies. This is the first study to characterize the transcriptome of human s-HSPCs in vivo, revealing activated expression of TEs and inflammatory genes.
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Senescencia Celular/genética , Citocinas/genética , Elementos Transponibles de ADN/genética , Regulación de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Adulto , Anciano , Citocinas/biosíntesis , Femenino , Regulación de la Expresión Génica/inmunología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/inmunología , Humanos , Inflamación , Interferones/biosíntesis , Interferones/genética , Masculino , Persona de Mediana Edad , Imitación Molecular/inmunología , Transcriptoma , Regulación hacia Arriba , Adulto JovenRESUMEN
Senescence, a state of permanent cell cycle arrest, can be induced by DNA damage. This process, which was initially described in fibroblasts, is now recognized to occur in stem cells. It has been well characterized in cell lines, but there is currently very limited data available on human senescence in vivo. We recently reported that the expression of transposable elements (TE), including endogenous retroviruses, was up-regulated along with inflammatory genes in human senescent hematopoietic stem and progenitor cells (HSPCs) in vivo. The mechanism of regulation of TE expression is not completely understood, but changes in DNA methylation and chromatin modifications are known to alter their expression. In order to elucidate the molecular mechanisms for TE up-regulation after senescence of HSPCs, we employed whole-genome bisulfite sequencing in paired senescent and active human HSPCs in vivo from healthy subjects. We found that the senescent HSPCs exhibited hypomethylated regions in the genome, which were enriched for TEs. This is the first report characterizing the methylome of senescent human HSPCs.
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We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger-encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.
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Leucemia Mieloide Aguda/genética , Mutación , Niño , Aberraciones Cromosómicas , Metilación de ADN , Humanos , TranscriptomaRESUMEN
The BCR-ABL1 fusion gene is caused by a translocation between chromosomes 9 and 22, resulting in an abnormal chromosome 22 (Philadelphia chromosome; Ph). Prior to the introduction of tyrosine kinase inhibitors (TKI), the presence of BCR-ABL1 conferred a poor prognosis in patients with acute lymphoblastic leukaemia (ALL). We compared the survival of Ph+ and Ph-ALL during the period when TKIs were universally available in the US for Ph+ALL, using a Surveillance, Epidemiology, and End Results (SEER) Database analysis. A total of 2694 patients with pre-B ALL (206 Ph+ALL; 2488 Ph-ALL) aged ≥18 years, who were diagnosed between 2010 and 2014, were identified in SEER registries. The median overall survival (OS) was 32 months in Ph+ALL (95% confidence interval [CI] 18 months-not reached) and 27 months (95% CI 24-30 months) in Ph-ALL (Log-rank test P-value 0·34). Older age was associated with worse prognosis in both Ph+ALL and Ph-ALL. Age-adjusted OS was inferior in Hispanics and African-Americans compared to non-Hispanic whites. Survival of pre-B ALL shows continued improvement with time. Philadelphia chromosome status does not confer poor prognosis in pre-B ALL in the TKI era: prognostic factors in pre-B ALL should be re-evaluated in the light of this finding.
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Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Etnicidad , Humanos , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Pronóstico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Sistema de Registros , Análisis de Supervivencia , Adulto JovenRESUMEN
The recently introduced Kallisto pseudoaligner has radically simplified the quantification of transcripts in RNA-sequencing experiments. We offer cloud-scale RNAseq pipelines Arkas-Quantification, and Arkas-Analysis available within Illumina's BaseSpace cloud application platform which expedites Kallisto preparatory routines, reliably calculates differential expression, and performs gene-set enrichment of REACTOME pathways . Due to inherit inefficiencies of scale, Illumina's BaseSpace computing platform offers a massively parallel distributive environment improving data management services and data importing. Arkas-Quantification deploys Kallisto for parallel cloud computations and is conveniently integrated downstream from the BaseSpace Sequence Read Archive (SRA) import/conversion application titled SRA Import. Arkas-Analysis annotates the Kallisto results by extracting structured information directly from source FASTA files with per-contig metadata, calculates the differential expression and gene-set enrichment analysis on both coding genes and transcripts. The Arkas cloud pipeline supports ENSEMBL transcriptomes and can be used downstream from the SRA Import facilitating raw sequencing importing, SRA FASTQ conversion, RNA quantification and analysis steps.
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Genomic transposable elements (TEs) comprise nearly half of the human genome. The expression of TEs is considered potentially hazardous, as it can lead to insertional mutagenesis and genomic instability. However, recent studies have revealed that TEs are involved in immune-mediated cell clearance. Hypomethylating agents can increase the expression of TEs in cancer cells, inducing 'viral mimicry', causing interferon signalling and cancer cell killing. To investigate the role of TEs in the pathogenesis of acute myeloid leukaemia (AML), we studied TE expression in several cell fractions of AML while tracking its development (pre-leukemic haematopoietic stem cells, leukemic stem cells [LSCs], and leukemic blasts). LSCs, which are resistant to chemotherapy and serve as reservoirs for relapse, showed significant suppression of TEs and interferon pathways. Similarly, high-risk cases of myelodysplastic syndrome (MDS) showed far greater suppression of TEs than low-risk cases. We propose TE suppression as a mechanism for immune escape in AML and MDS. Repression of TEs co-occurred with the upregulation of several genes known to modulate TE expression, such as RNA helicases and autophagy genes. Thus, we have identified potential pathways that can be targeted to activate cancer immunogenicity via TEs in AML and MDS.