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While optical microscopy inspection of blood films and bone marrow aspirates by a hematologist is a crucial step in establishing diagnosis of acute leukemia, especially in low-resource settings where other diagnostic modalities are not available, the task remains time-consuming and prone to human inconsistencies. This has an impact especially in cases of Acute Promyelocytic Leukemia (APL) that require urgent treatment. Integration of automated computational hematopathology into clinical workflows can improve the throughput of these services and reduce cognitive human error. However, a major bottleneck in deploying such systems is a lack of sufficient cell morphological object-labels annotations to train deep learning models. We overcome this by leveraging patient diagnostic labels to train weakly-supervised models that detect different types of acute leukemia. We introduce a deep learning approach, Multiple Instance Learning for Leukocyte Identification (MILLIE), able to perform automated reliable analysis of blood films with minimal supervision. Without being trained to classify individual cells, MILLIE differentiates between acute lymphoblastic and myeloblastic leukemia in blood films. More importantly, MILLIE detects APL in blood films (AUC 0.94 ± 0.04) and in bone marrow aspirates (AUC 0.99 ± 0.01). MILLIE is a viable solution to augment the throughput of clinical pathways that require assessment of blood film microscopy.

For two decades, leukaemia stem cells (LSCs) in chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) have been advanced paradigms for the cancer stem cell field. In CML, the acquisition of the fusion tyrosine kinase BCR–ABL1 in a haematopoietic stem cell drives its transformation to become a LSC. In AML, LSCs can arise from multiple cell types through the activity of a number of oncogenic drivers and pre-leukaemic events, adding further layers of context and genetic and cellular heterogeneity to AML LSCs not observed in most cases of CML. Furthermore, LSCs from both AML and CML can be refractory to standard-of-care therapies and persist in patients, diversify clonally and serve as reservoirs to drive relapse, recurrence or progression to more aggressive forms. Despite these complexities, LSCs in both diseases share biological features, making them distinct from other CML or AML progenitor cells and from normal haematopoietic stem cells. These features may represent Achilles’ heels against which novel therapies can be developed. Here, we review many of the similarities and differences that exist between LSCs in CML and AML and examine the therapeutic strategies that could be used to eradicate them.This Review discusses many of the similarities and differences between leukaemia stem cells (LSCs) in chronic myeloid leukaemia and acute myeloid leukaemia and examines the therapeutic strategies that could be used to eradicate these LSCs.

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1 / CEBPA or RAS - RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR , homologous IDH gene, and TET2 . These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML. The regulation of resistance to IDH inhibitors in acute myeloid leukaemia is not completely understood. Here the authors reveal with integrative multi-omics analyses that stemness features are major drivers of primary resistance, while high-risk mutations drive acquired resistance.

BackgroundMany high-dose groups demonstrate increased leukaemia risks, with risk greatest following childhood exposure; risks at low/moderate doses are less clear.MethodsWe conducted a pooled analysis of the major radiation-associated leukaemias (acute myeloid leukaemia (AML) with/without the inclusion of myelodysplastic syndrome (MDS), chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL)) in ten childhood-exposed groups, including Japanese atomic bomb survivors, four therapeutically irradiated and five diagnostically exposed cohorts, a mixture of incidence and mortality data. Relative/absolute risk Poisson regression models were fitted.ResultsOf 365 cases/deaths of leukaemias excluding chronic lymphocytic leukaemia, there were 272 AML/CML/ALL among 310,905 persons (7,641,362 person-years), with mean active bone marrow (ABM) dose of 0.11 Gy (range 0–5.95). We estimated significant (P < 0.005) linear excess relative risks/Gy (ERR/Gy) for: AML (n = 140) = 1.48 (95% CI 0.59–2.85), CML (n = 61) = 1.77 (95% CI 0.38–4.50), and ALL (n = 71) = 6.65 (95% CI 2.79–14.83). There is upward curvature in the dose response for ALL and AML over the full dose range, although at lower doses (<0.5 Gy) curvature for ALL is downwards.DiscussionWe found increased ERR/Gy for all major types of radiation-associated leukaemia after childhood exposure to ABM doses that were predominantly (for 99%) <1 Gy, and consistent with our prior analysis focusing on <100 mGy.

ENL, identified in a genome-scale loss-of-function screen as a crucial requirement for proliferation of acute leukaemia, is required for leukaemic gene expression, and its YEATS chromatin-reader domain is essential for leukaemic growth. Gene control in acute leukaemia Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene give rise to acute myeloid leukaemia (AML). Here, James Bradner and colleagues perform a genome-scale loss-of-function screen using CRISPR–Cas9 technology in MLL-AF4 AML cells. They find that the ENL gene is critical for cell proliferation and use a chemical genetic strategy of targeted protein degradation to show that loss of ENL suppresses transcriptional activation as well as leukaemic growth. ENL-dependent leukaemic growth depends on its YEATS chromatin reader domain, indicating that competitive antagonists of the YEATS domain could be potential therapeutics for AML. A related paper in this week's issue of Nature from Xiaobing Shi and colleagues provides insights into the function of the ENL YEATS domain in recognizing acetylated histones. Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome 1 . The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control 2 . Despite recent progress made in targeting chromatin regulators in cancer 3 , available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR–Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo . To explain the mechanistic role of ENL in leukaemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukaemic growth. Overall, these findings identify a dependency factor in acute leukaemia and suggest a mechanistic rationale for disrupting the YEATS domain in disease.

Minimal residual disease (MRD) detected before hematopoietic cell transplantation (HCT) is associated with adverse outcomes in patients with high-risk acute leukemia. However, the ideal time points for post-transplant MRD assessment and the clinical significance of low levels of residual disease in this context are unclear. We conducted a prospective real-world analysis of high-sensitivity flow cytometry MRD performed before and after transplant (at days 30, 60 and 100) in 77 acute leukemia patients. The aim was to evaluate the kinetics of disease elimination and correlate it with transplant outcomes. Pre-transplant MRD was negative in 42 (MRD-) and positive in 35 patients (MRD+). Post-transplant MRD assessment was feasible at day 30 ( n  = 30, 38.9%), day 60 ( n  = 27, 35.0%) and day 100 ( n  = 60, 77.9%). Relapses occurred in 8 patients in the MRD + group (22.9%) and three in the MRD-negative group (7.1%), p  = 0.02. Pre-transplant MRD correlated with a decrease in overall survival (OS; 87.9% MRD- vs. 54.0% MRD+) and event-free survival (EFS; 85.3% MRD- vs. 51.1% MRD+), p  = 0.001. Cumulative incidence of relapse (CIR) was 17.5% in MRD + vs. 2.6% in MRD- ( p =  0.049). Non-relapse mortality (NRM) was 31.4% in MRD + vs. 12.1% in MRD- ( p =  0.019). One-year OS was higher in patients with negative MRD at d100 (92.4%, 95% CI: 0.81–0.971) than positive d100 MRD (53.3%, 95% CI: 0.177–0.796), p <  0.0001. Disease status and d100 MRD were associated with OS, EFS and CIR. Differences in NRM between leukemia types (ALL: 18.9% MRD- vs. 50% MRD+, and AML 0% MRD- vs. 21.7% MRD+, p  = 0.0158) were also observed. In conclusion, pre-transplant MRD assessed by highly sensitive flow cytometry accurately identified patients with adverse prognoses. Persistent MRD after HCT could predict relapse with high specificity and clinical sensitivity. These results highlight the importance of incorporating peri-transplant MRD kinetics into the routine treatment of acute leukemia, particularly in low/middle-income countries.

This study aimed to observe the safety and clinical efficacy of early application of ruxolitinib to prevent acute graft-versus-host disease (aGVHD) after alternative donor transplantation in acute leukemia. There were 57 patients undergoing allo-HSCT at the Affiliated Cancer Hospital of Zhengzhou University from July 2017 to October 2019. They were divided into control(16 patients) and ruxolitinib (41 patients) groups. For aGVHD prophylaxis, the control group received post-transplantation cyclophosphamide, antithymocyte globulin-Fresenius, cyclosporine A, and mycophenolate mofetil, while in the ruxolitinib group, ruxolitinib 5 mg/d in adults or 0.07–0.1 mg/(kg d) in children was administered from the day of neutrophil engraftment to 100 days post-transplantation based on control group. We found 55 patients had successful reconstitution of hematopoiesis; No significant difference was found in cGVHD, hemorrhagic cystitis, pulmonary infection, intestinal infection, Epstein-Barr virus infection, cytomegalovirus infection, relapse, death, and nonrelapse mortality. The incidences of aGVHD (50 vs. 22%, P  = 0.046) and grade II–IV aGVHD (42.9 vs. 12.2%, P  = 0.013) were significantly higher in the control group than in the ruxolitinib group. No significant differences were observed in overall survival ( P  = 0.514), disease-free survival ( P  = 0.691), and cumulative platelet transfusion within 100 days post-transplantation between two groups. This suggests early application of ruxolitinib can reduce the incidence and severity of aGVHD and patients are well tolerated.

Acute myeloid and lymphoid leukemias often harbor chromosomal translocations involving the KMT2A gene, encoding the KMT2A lysine methyltransferase (also known as mixed-lineage leukemia-1), and produce in-frame fusions of KMT2A to other chromatin-regulatory proteins. Here we map fusion-specific targets across the genome for diverse KMT2A oncofusion proteins in cell lines and patient samples. By modifying CUT&Tag chromatin profiling for full automation, we identify common and tumor-subtype-specific sites of aberrant chromatin regulation induced by KMT2A oncofusion proteins. A subset of KMT2A oncofusion-binding sites are marked by bivalent (H3K4me3 and H3K27me3) chromatin signatures, and single-cell CUT&Tag profiling reveals that these sites display cell-to-cell heterogeneity suggestive of lineage plasticity. In addition, we find that aberrant enrichment of H3K4me3 in gene bodies is sensitive to Menin inhibitors, demonstrating the utility of automated chromatin profiling for identifying therapeutic vulnerabilities. Thus, integration of automated and single-cell CUT&Tag can uncover epigenomic heterogeneity within patient samples and predict sensitivity to therapeutic agents. Automated and single-cell CUT&Tag is used to characterize the effects of KMT2A fusion proteins on chromatin in human primary leukemia samples, identifying oncogenic networks and fusion-specific therapeutic vulnerabilities.

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53 , FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1 , the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia. Analysis of genomic and clinical features of acute erythroid leukemia in comparison to other myeloid disorders supports its distinct classification, defines subgroups and suggests therapeutic vulnerabilities.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosome 21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4 - and KMT2A -rearranged subtypes separate into CEBPA/FLT3 - or NFATC4 -expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes. A genomic and transcriptomic analysis of 2,754 childhood acute lymphoblastic leukemias identifies 376 putative driver genes, and associations between disease subtypes and prognosis.