Who truly benefits from gilteritinib combinations in FLT3-mutated relapsed-refractory(R/R) AML: a Canadian single center analysis.

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Plasma lipid levels predict chemotherapy response and survival in acute myeloid leukemia.

Acute myeloid leukemia (AML) is characterized by a low five-year survival rate. Despite having many clinical metrics to assess patient prognosis, there remain opportunities to improve risk stratification. We hypothesized that an underexplored resource to examine AML patient prognosis is the plasma metabolome.

Activation of a nongenetic AHR-ELMSAN1 axis optimizes BET-targeting therapy and suppresses leukemia stem cells in preclinical models.

Developing strategies to enhance the response to bromodomain and extraterminal domain (BET) inhibitors and effectively eradicate cancer stem cells would represent a major cancer treatment advance against leukemia. Through a functional CRISPR screen, we identified the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, as a critical regulator of MYC expression and BET inhibitor sensitivity in human acute myeloid leukemia (AML). Constitutive or pharmacological activation of AHR repressed MYC and synergized with BET inhibitors to inhibit MYC transcription and suppress leukemia growth across diverse AML models.

Identifying Risk Factors and Outcome for CNS Involvement in AML.

Background: Central nervous system infiltration (CNS+) leads to serious complications in AML. Molecular characteristics associated with CNS disease is not well defined.

Material And Methods: 259 patients received lumbar puncture (LP) and prophylaxis intrathecal (IT) chemotherapy based on neurological symptoms and / or hyperleukocytosis RESULTS: : 31 (11.

Real-world validation study of the LSC17 score for risk prediction in patients with newly diagnosed acute myeloid leukemia.

Acute myeloid leukemia (AML) patients exhibit diverse molecular and cytogenetic changes with heterogeneous outcomes. The functionally-derived LSC17 gene expression score has demonstrated strong prognostic significance in retrospective analyses of adult and pediatric AML cohorts, where above-median scores are associated with worse outcomes compared to below-median scores in intensively-treated patients. Here we used a laboratory-developed clinically-validated NanoStringbased LSC17 assay to test the prognostic value of the LSC17 score in a prospective multicentre study of 276 newly-diagnosed AML patients.

Risk Assessment With Ultra-Low-Pass Whole-Genome Sequencing of Cell-Free DNA for Large B-Cell Lymphoma.

Purpose: Although deep targeted DNA sequencing of liquid biopsies has shown prognostic utility in large B-cell lymphoma (LBCL), the routine clinical adoption of these assays remains limited because of their high costs.

Materials And Methods: Here, leveraging a well-annotated cohort encompassing both frontline and relapsed/refractory (R/R) LBCL, we profiled patient plasma samples with two complementary modalities-ultra-low-pass whole-genome sequencing (ULP-WGS) and deep targeted DNA sequencing, the former being a cost-effective method to profile large scale chromosomal abnormalities and estimate tumor burden.

Results: Our findings revealed a strong association of high cell-free tumor burden by both genomic profiling modalities with established measures of tumor burden and patient survival.

Mutant cooperates with or to drive distinct myeloid diseases and molecular outcomes.

In human acute myeloid leukemia (AML), mutations of isocitrate dehydrogenase-1 () often co-occur with mutations, and less frequently with mutations. To investigate whether the effects of mutation differ according to the specific co-occurring mutation, we generated two strains of double knock-in mutant mice. combined with induced overt AML, whereas plus resulted in -driven myelo- or lymphoproliferation that was minimally affected by and rarely generated AML.

Single-cell Transcriptional Atlas of Human Hematopoiesis Reveals Genetic and Hierarchy-Based Determinants of Aberrant AML Differentiation.

Unlabelled: Therapeutic targeting of acute myeloid leukemia (AML) is hampered by intra- and inter-tumoral cell state heterogeneity. To develop a more precise understanding of AML cell states, we constructed a reference atlas of human hematopoiesis from 263,159 single-cell transcriptomes spanning 55 cellular states. Using this atlas, we mapped more than 1.

Single-cell RNA sequencing of human double-negative T cells reveals a favorable cellular signature for cancer therapy.

Background: Allogeneic double-negative T-cell (DNT) therapy has emerged as a novel, off-the-shelf cellular treatment with clinical feasibility, safety, and promising efficacy against leukemia. However, the biology of DNTs is less well characterized, and how DNT therapy distinguishes from conventional γδ T-cell therapy remains unclear. Collectively, this hinders our ability to bolster DNT functionalities in cancer therapy.

Safety, tolerability, and pharmacokinetics of ASP1235 in relapsed or refractory acute myeloid leukemia: A phase 1 study.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. Although new agents including targeted therapies for relapsed or refractory (R/R) AML have been introduced, poor outcomes remain, requiring the need for novel approaches. One novel approach is the use of antibody-drug conjugates (ADCs).

Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.

OxPhos inhibitors have struggled to show a clinical benefit because of their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to acute myeloid leukemia (AML) mitochondria. Unlike healthy cells that couple respiration to ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP.

Blood-based proteomic profiling identifies OSMR as a novel biomarker of AML outcomes.

Inflammation is increasingly recognized as a critical factor in acute myeloid leukemia (AML) pathogenesis. We performed blood-based proteomic profiling of 251 inflammatory proteins in 543 patients with newly diagnosed AML. Using a machine learning model, we derived an 8-protein prognostic score termed the leukemia inflammatory risk score (LIRS).

Maintenance therapy with the FMS-like tyrosine kinase 3 inhibitor gilteritinib in patients with FMS-like tyrosine kinase 3-internal tandem duplication acute myeloid leukemia: A phase 2 study.

Background: The GOSSAMER phase 2 study assessed the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib as maintenance therapy in patients with FLT3-internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML) in first complete remission without previous hematopoietic stem cell transplantation (HSCT).

Methods: Patients had to be within 2 months of their last consolidation cycle and have completed the recommended number of cycles per local practice. FLT3 inhibitors were allowed only during induction and/or consolidation.

SOCS1 Protects Acute Myeloid Leukemia against Allogeneic T Cell-Mediated Cytotoxicity.

Our investigation of the SOCS1 pathway in AML and T-cell interactions provides insights into potential mechanisms of resistance of AML to allogeneic hematopoietic stem cell transplantation and demonstrates the potential of targeting SOCS1 and its downstream mediators to enhance antileukemic T-cell activity. See related commentary by Fry, p. 157.

Dietary Modulation of Fatty Acid Oxidation Imparts Stem Cell Protection in Bone Marrow.

Hematopoietic stem cells (HSCs) maintain production of all functional blood cells and are located within the bone marrow. In pathological conditions, such as obesity or leukemia, changes in these cells contribute to disease pathophysiology. In this study, we examined the impact of metabolic modulation of stem and progenitor cells within the bone marrow during diet-induced obesity (DIO) and leukemia relapse.

Allogeneic DNT cell therapy synergizes with T cells to promote anti-leukemic activities while suppressing GvHD.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a second-line treatment with curative potential for leukemia patients. However, the prognosis of allo-HSCT patients with disease relapse or graft-versus-host disease (GvHD) is poor. CD4 or CD8 conventional T (Tconv) cells are critically involved in mediating anti-leukemic immune responses to prevent relapse and detrimental GvHD.

FLT3 is genetically essential for ITD-mutated leukemic stem cells but dispensable for human hematopoietic stem cells.

Leukemic stem cells (LSCs) fuel acute myeloid leukemia (AML) growth and relapse, but therapies tailored toward eradicating LSCs without harming normal hematopoietic stem cells (HSCs) are lacking. FMS-like tyrosine kinase 3 (FLT3) is considered an important therapeutic target due to frequent mutation in AML and association with relapse. However, there has been limited clinical success with FLT3 drug targeting, suggesting either that FLT3 is not a vulnerability in LSC or that more potent inhibition is required, a scenario where HSC toxicity could become limiting.

CEBPA repression by MECOM blocks differentiation to drive aggressive leukemias.

Acute myeloid leukemias (AMLs) have an overall poor prognosis with many high-risk cases co-opting stem cell gene regulatory programs, yet the mechanisms through which this occurs remain poorly understood. Increased expression of the stem cell transcription factor, MECOM, underlies one key driver mechanism in largely incurable AMLs. How MECOM results in such aggressive AML phenotypes remains unknown.

Tissue Prior to the Initial Hematoxylin-Eosin Section Demonstrates Value as an Alternative Source of DNA for Molecular Testing.

Context.—: Small biopsies are used for histologic, immunophenotypic, cytogenetic, molecular genetic, and other ancillary studies. Occasionally, this diagnostic tissue is exhausted before molecular testing can be performed.

Acute myeloid leukemia drug-tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing.

Resistance to chemotherapy remains a major hurdle to the cure of patients with acute myeloid leukemia (AML). Recent studies indicate that a minority of malignant cells, termed drug-tolerant persisters (DTP), stochastically upregulate stress pathways to evade cell death upon acute exposure to chemotherapy without acquiring new genetic mutations. This chemoresistant state is transient and the cells return to the baseline state after removal of chemotherapy.

Outcome of adolescents and young adult acute myeloid leukemia patients compared with middle-aged patients: A single centre retrospective experience.

Adult acute myeloid leukemia (AML) patients under the age of 60 often receive similar intensive treatments, while outcomes between the adolescent and young adult (AYA) age group (18-39) and middle-aged adults (40-60 years) were seldom reported. We aim to study the characteristics and outcomes of AYA patients in comparison to middle-aged adults. A retrospective analysis was performed on AYA patients treated at Princess Margaret Cancer Center between 2008 and 2018.

Spermidine metabolism regulates leukemia stem and progenitor cell function through KAT7 expression in patient-derived mouse models.

Acute myeloid leukemia (AML) is a devastating disease initiated and maintained by a rare subset of cells called leukemia stem cells (LSCs). LSCs are responsible for driving disease relapse, making the development of new therapeutic strategies to target LSCs urgently needed. The use of mass spectrometry-based metabolomics profiling has enabled the discovery of unique and targetable metabolic properties in LSCs.