Leukemia and Lymphoma Awareness Month

The molecular heterogeneity of KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) remains poorly characterised. Here, the authors perform multi-omics analysis for 84 ALL patients and suggest 5 distinct subgroups for risk stratification and personalised treatment.’

The development of IDH variant inhibitors is a breakthrough as it is the first time metabolism has been successfully targeted by small molecule drugs in cancer. Here the authors report studies on resistance to the pioneer drug ivosidenib leading to identification of inhibitors retaining activity.

Classification and risk-stratification for Acute Myeloid Leukemia (AML) at diagnosis are primarily based on cytogenetics and only a few gene mutations. Here, the authors study the genomic landscape of 3653 AML patients and characterize 16 non-overlapping molecular subgroups of clinical relevance for disease classification and risk prognostication.

The oxysterol-binding protein-related protein 4 (ORP4L) is expressed in T-cell acute lymphoblastic leukemia and is required for leukemogenesis. Here the authors show that ORP4L orchestrates the transport of the phospholipid PI(4)P from Golgi to the plasma membrane, contributing to PI3K/AKT hyperactivation and T-cell leukemogenesis.

Healthy T cells are polyclonal, while malignant T cells are developing via clonal expansion. Here authors show that T cell tumours could be eradicated by chimeric antigen receptor T cells targeting the T cell receptor (TCR) β-chain that is specific to malignant T cells, while healthy T cells using diverse TCR β-chains are spared.

Rare tumour specific mutations in patient samples act as markers to monitor the course of disease. Here the authors report superRCA assays for rapid, highly specific detection of DNA sequence variants present at very low frequencies in DNA samples with flow cytometry readout; they use this on AML patients.

The bone tumour microenvironment plays an essential role in multiple myeloma (MM) development. Here, the authors show that bone collagen degradation provides glycine to support MM progression through glutathione and purine synthesis.

Leukemic stem cells (LSCs) drive chemoresistance and relapse in acute myeloid leukemia. Here, the authors show that the splicing factor RBM17 supports LSCs through avoiding nonsense-mediated decay of pro-leukaemic factors such as the translation initiation factor EIF4A2.

Activating FLT3 mutations are the most common mutations in AML. Here, the authors explore the relationship between the FLT3/ITD allelic ratio and prognosis in pediatric AML patients and identify an optimal threshold to stratify patients.

Ph⁺ and Ph-like B-ALL remain poor prognosis leukemias. VAV3, a guanine nucleotide exchange factor, is activated and overexpressed in these leukemias. Here the authors reveal that leukemic VAV3 is predominantly nuclear. Nuclear VAV3, through its guanine nucleotide exchange factor and its effector nuclear RAC2, controls the repressive transcriptional activity of the polycomb repression complex-1 via nuclear AKT/PHLPP2 regulated BMI1.

CDK2 can drive the proliferation of cancer cells. Here, the authors screened for a non-ATP competitive inhibitor of the CDK2/cylinA complex and find that Homoharringtonine can disrupt the complex and promote the degradation of CDK2.

Notch1 is frequently activated promoting T-cell acute lymphoblastic leukaemia (T-ALL). Here, the authors show that Notch1 induces oxidative phosphorylation dependency in T-ALL and synergism when inhibiting both mitochondrial complex I and glutaminolysis in preclinical murine and human xenograft models.

Mitochondrial metabolism has been associated with tumourigenesis in acute myeloid leukaemia (AML) and currently considered as a potential therapeutic target. Here, the authors show, in patients with AML, that germline mutations in mitochondrial complex I are mutually exclusive with somatic mutations in the metabolic enzyme IDH1, and find IDH1 mutant cells have increased sensitivity to complex I inhibitors.

The role of gut microbiota in acute myeloid leukaemia (AML) remains unclear. Here, the authors show disordered gut microbiota and reduced butyrate cause intestinal barrier damage in AML mice, with increased plasma LPS that accelerates AML progression.

CD123, the interleukin-3 receptor alpha chain, is aberrantly expressed in acute myeloid leukemia blasts and leukemia stem cells. Here the authors report the design and characterize the anti-tumor activity of allogeneic CD123-targeted CAR-T cells as a therapeutic approach for acute myeloid leukemia.

Inhibition of specific metabolic pathways often drives metabolic adaptation. Here, the authors show that FLT3-ITD + acute myeloid leukemia cells are OXPHOS-driven, and inhibition of complex II activity results in increased lactate influx to drive respiration, which creates a targetable vulnerability.

Non-coding variants can regulate transcription factor binding and gene expression at variable chromatin modules. Here, the authors show that a germline variant induces transcription factor nucleation through chromatin compaction leading to AXIN2 up-regulation and is associated to better prognosis in chronic lymphocytic leukaemia.

Identifying effective drug combinations to treat cancer is a challenging task, either experimentally or computationally. Here, the authors develop a bipartite network modelling approach to propose drug combination strategies in acute myeloid leukaemia using patient and cell line drug screening data.

T cell large granular lymphocytic leukemia (T-LGLL) is a lymphoproliferative disorder involving clonally expanded T cell clones and is not fully understood. Here the authors show that the rest of the immune repertoire is interconnected with the T-LGLL clonotype(s) and is more mature, cytotoxic and clonally restricted than in other cancers and autoimmune disorders.

T cell large granular lymphocyte leukemia (T-LGLL) and the cellular phenotype underlying response to therapy is not well understood. Here the authors use single cell sequencing to better understand changes in T cell clonal frequency and gene expression before and after therapy in T-LGLL.

Combining cytarabine and mitoxantrone with the tricarboxylic acid cycle inhibitor devimistat has been reported in a phase I clinical trial with relapsed or refractory acute myeloid leukaemia (AML). Here, the authors report the outcomes of a phase II study, analyse samples from both phases and perform preclinical analyses that show mitochondrial fission or autophagy inhibition sensitizes AML cells to devimistat.

Childhood acute lymphoblastic leukemia is characterised by a range of genetic aberrations. Here, the authors use multi-omics profiling of ALL cell lines to connect molecular phenotypes and drug responses to provide an interactive resource of drug sensitivity.

The genomic landscape of pediatric acute myeloid leukemia (AML) has mostly been characterised for Western populations. Here, the authors identify potential driver alterations in Chinese pediatric AML, which differ from Western populations, and propose a prognostic risk classification model.

Clonal dynamics and selection have not been fully understood in patient-derived xenografts (PDX) of acute myeloid leukemia (AML). Here, the authors generate 160 AML-PDX models to track the clonal dynamics of primary and relapsed AML, and find selectively enriched subclones that are associated with resistance to therapy.

Circulating microbiome has been very little studied for blood malignancies. Here, the authors show specific microbiome signatures in the blood are associated with different types of myeloid malignancies and specific genetic mutations.

The success rate of chimeric antigen receptor T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here authors show that therapeutic response in multiple myeloma, acute lymphoblastic leukemia and non-Hodgkin lymphoma, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.

Modelling of aggressive lymphomas, such as double hit lymphoma, has been challenging. Here the authors engineer a CRISPR activation mouse to enable the generation of these aggressive lymphomas and identify the pro-survival BCL-2 protein A1 as a venetoclax resistance factor.

Survival outcomes in Burkitt lymphoma differ between adult and paediatric patients. Here, the authors show differences in mutational frequencies between age groups, and a transition between mutational profiles which occurs between 25 and 40 years.

Primary lymphomas of the central nervous system (PCNSL) are defined as diffuse large B-cell lymphomas (DLBCL) confined to the CNS. Here, the authors complete whole genome sequencing and RNA-seq to characterize 51 PCNSLs, and find common mutations in immune pathways and upregulated TERT expression and find distinct pathway differences between DLBCL and other primary CNS lymphomas.

IRF4 is a regulator of immune function, and is overexpressed in lymphoid neoplasms. Here, the authors utilise single cell RNA-seq to show the abundance of double-negative T cells in IRF4 driven zebrafish tumour models, and identify sensitivity of these tumours to BRD inhibition.

Targeting integrin-mediated retention of malignant B cells in their protective microenvironment is an efficacious treatment for lymphoma and leukemia. Here, the authors present an unbiased loss-of-adhesion CRISPR screening method, identifying therapeutic targets for these B-cell malignancies.

Cutaneous T cell lymphomas (CTCL) are still poorly characterised at the molecular and single-cell level. Here, the authors analyse CTCL patient samples using single-cell RNA-seq, TCR and whole-exome sequencing, revealing the molecular profiles of malignant T cells and their association with the microenvironment and clinical outcomes.

Vaccination is effective in preventing severe COVID-19 symptoms. Here the authors monitor patients with hematopoietic malignancy to find the third dose of the mRNA vaccine, BNT162b2, only boosts the humoral immunity in those showing responses to 2nd dose vaccination but can induce an independent T-cell response in a fraction of seronegative patients.

SUMOylation is a post-translational modification that has been shown to be altered in cancer. Here, the authors show that loss of the SUMO isopeptidase SENP6 leads to unrestricted SUMOylation and genomic instability promoting lymphomagenesis and generating vulnerability to PARP inhibition.

Antigen escape represents a potential drawback of chimeric antigen receptor T cell (CAR-T) therapy targeting a single tumor-associated antigen. To reduce the risk of antigen escape, here the authors report the design and characterization of a BAFF ligand CAR-T that can recognize three different receptors (BAFF-R, BCMA and TACI), demonstrating in vitro and in vivo cytotoxicity against multiple B cell cancer models.

Strategies to address the challenges associated with product manufacturing can improve chimeric antigen receptor (CAR) cell–based therapeutics. Here the authors report the results of two clinical trials in patients with B-cell malignancies, showing that place-of-care manufacturing has a low production failure rate with CD19-directed CAR-T cell products inducing high remission rates.

PD-1 blockade is effective for only a subset of patients with cutaneous T cell lymphomas. Here, the authors report a spatial biomarker that uses immune and cancer cell topography to predict response to PD-1 blockade in this disease.

Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma often with poor prognosis. To identify genes defining ALCL cell state and dependencies, the authors here characterize ALCL-specific super-enhancers and describe the BATF3/IL-2R−module as a therapeutic opportunity for ALCL.

Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.

Characterising the clonal architecture of Adult T-cell leukemia-lymphoma (ATL) remains crucial. Here, the authors develop a capture-based sequencing panel and use deep DNA and single cell RNA sequencing and report distinct genomic and transcriptomic features associated with subclonal evolution.

Peripheral T cell lymphoma (PTCL) not otherwise specified (NOS) is a subgroup of PTCL, which has no distinctive features and is poorly characterized at the genetic level. Here, the authors identify two fusion transcripts that activate T cell receptor complex signalling and confer therapeutic vulnerability in PTCL-NOS.

Mantle cell lymphoma can be refractory to treatment. Here, the authors used single cell sequencing to study the tumours of patients that were responsive and resistant to treatment and find gains of 17q in resistant tumours, which they attribute to increased expression of Birc5 and validate these findings in mouse models of the disease.

CAR-T cell therapy targeting CD19 is not as efficient to treat lymphoma with nodal dissemination as it is for B cell leukaemia. Here, the authors generate CAR-T cells against CXCR5 and show they inhibit tumour growth by depleting both B and follicular T helper cells in lymphoma models.

Primary effusion lymphoma (PEL) has a very poor prognosis. Here, the authors perform H3K27ac HiChIP in PEL cells and generate the PEL enhancer connectome, linking enhancers and promoters in PEL, as well as super-enhancers to dependency factors.

c-MYC is often deregulated in human cancers including lymphomas. Here, the authors show that a member of the pseudokinase family, tribbles homologue 3 (TRIB3), interacts with c-MYC to suppress c-MYC ubiquitination and degradation, leading to increased proliferation and self-renewal of lymphoma cells.

N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients.

Therapy-induced senescence reflects a biological effector principle that is underrecognized in lesion-focused cancer precision medicine. Here the authors utilize mouse lymphoma genetics to functionally dissect senescence and cross-species apply a novel senescence-based prognosticator to lymphoma patients.

Oncogene addiction is considered as a cancer cell-autonomous phenomenon, but can also influence the host immune system. Here the authors show that MYC-driven lymphomagenesis is associated with a block in the maturation and effector functions of natural killer cells as a mechanism of tumor escape from immunosurveillance.

The transcriptional regulator PRDM15 is expressed at low levels in normal tissues but overexpressed in B-cell lymphomas. Here, the authors show that PRDM15 depletion does not affect adult somatic cell homeostasis but leads to a metabolic crisis which impairs B-cell lymphomagenesis.

Nodular lymphocyte-predominant Hodgkin lymphoma with IgD+ lymphocyte-predominant (LP) cells is a rare clinical distinct lymphoma subset of B-cell origin. Here the authors show that antigens expressed by Moraxella catarrhalis are recognized by B cell receptors of IgD+ LP cells, suggesting the contribution of chronic antigen stimulation to lymphomagenesis.