Impact of the clinical nurse specialist role for the myeloproliferative neoplasm program: Part Two - The team and patient care experiences.

Myeloproliferative neoplasms (MPN) are a group of rare clonal disorders of hematopoietic progenitor cells associated with disease- related symptoms, thrombotic events, and risk of transformation to acute myeloid leukemia (Tefferi, 2021). Their relative rarity and complexity of care led to the establishment of the MPN program at the Princess Margaret (PM) Cancer Centre, Toronto, Canada. The MPN program utilizes a shared-care model wherein partnering with local hematologists (shared-care partners) ensures that patients have access to a MPN specialist while continuing to receive care close to home.

Impact of the clinical nurse specialist role for the myeloproliferative neoplasm program: Part One - From timeliness of triage to cost-saving.

Myeloproliferative neoplasms (MPNs) are a group of rare clonal disorders of hematopoietic progenitor cells associated with disease-related symptoms, thrombotic events, and risk of transformation to acute myeloid leukemia (Tefferi, 2021). The relative rarity and complexity of care led to the establishment of the MPN program at the Princess Margaret (PM) Cancer Centre. The MPN program utilizes a shared-care model wherein partnering with local hematologists (shared-care partners) ensures that patients have access to an MPN specialist while continuing to receive care close to home (Cheung et al.

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.

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.

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.

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).

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.

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.

Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes.

Advancements in genomics are transforming the clinical management of chronic myeloid leukemia (CML) toward precision medicine. The impact of somatic mutations on treatment outcomes is still under debate. We studied the association of somatic mutations in epigenetic modifier genes and activated signaling/myeloid transcription factors (AS/MTFs) with disease progression and treatment failure in patients with CML after tyrosine kinase inhibitor (TKI) therapy.

Single-cell transcriptional mapping reveals genetic and non-genetic determinants of aberrant differentiation in AML.

In acute myeloid leukemia (AML), genetic mutations distort hematopoietic differentiation, resulting in the accumulation of leukemic blasts. Yet, it remains unclear how these mutations intersect with cellular origins and whether they converge upon similar differentiation patterns. Single-cell RNA sequencing (scRNA-seq) has enabled high-resolution mapping of the relationship between leukemia and normal cell states, yet this application is hampered by imprecise reference maps of normal hematopoiesis and small sample sizes among patient cohorts.

Outcomes of intensive and nonintensive blast-reduction strategies in accelerated and blast-phase MPN.

Transformation of BCR::ABL1-negative myeloproliferative neoplasms (MPN) to an accelerated or blast phase is associated with poor outcomes. The efficacy of acute myeloid leukemia (AML)-type intensive and nonintensive hypomethylating agent-based regimens is not well studied. We therefore performed a retrospective analysis of patients with MPN-AP/BP (N = 138) treated with intensive (N = 81) and nonintensive (N = 57) blast-reduction strategies.

Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia.

Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature.

Transcriptomic classes of BCR-ABL1 lymphoblastic leukemia.

In BCR-ABL1 lymphoblastic leukemia, treatment heterogeneity to tyrosine kinase inhibitors (TKIs), especially in the absence of kinase domain mutations in BCR-ABL1, is poorly understood. Through deep molecular profiling, we uncovered three transcriptomic subtypes of BCR-ABL1 lymphoblastic leukemia, each representing a maturation arrest at a stage of B-cell progenitor differentiation. An earlier arrest was associated with lineage promiscuity, treatment refractoriness and poor patient outcomes.