Clonal hematopoiesis in large granular lymphocytic leukemia.

Past studies described occasional patients with myeloid neoplasms (MN) and coexistent large granular lymphocytic leukemia (LGLL) or T-cell clonopathy of unknown significance (TCUS), which may represent expansion of myeloid clonal hematopoiesis (CH) as triggers or targets of clonal cytotoxic T cell reactions. We retrospectively analyzed 349 LGLL/TCUS patients, 672 MN patients, and 1443 CH individuals to establish the incidence, genetic landscape, and clinical phenotypes of CH in LGLL. We identified 8% of cases overlapping with MN, while CH was found in an additional 19% of cases (CH + /LGLL) of which TET2 (23%) and DNMT3A (14%) were the most common.

Dissecting the genomic traits and clinical course of secondary myelodysplastic syndrome following aplastic anaemia: A milestone.

Dissecting the genomic traits and clinical course of secondary myelodysplastic syndrome following aplastic anaemia is a milestone. The report by Li and colleagues investigates determinants of evolution to myelodysplastic syndrome and acute myeloid leukaemia in patients with aplastic anaemia and paroxysmal nocturnal haemoglobinuria with a specific focus on post-transplant outcomes. Commentary on: Li et al.

Correction: Guarnera et al. Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives. 2024, , 9023.

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Landscape of biallelic DNMT3A mutant myeloid neoplasms.

DNA methyltransferase 3 A mutations (DNMT3A) are frequent in myeloid neoplasia (MN) and mostly heterozygous. However, cases with multiple DNMT3A can be also encountered but their clinical and genetic landscape remains unexplored. We retrospectively analyzed 533 cases with DNMT3A identified out of 5,603 consecutive MNs, of whom 8.

Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives.

(alias: mixed-lineage leukemia []) gene mapping on chromosome 11q23 encodes the lysine-specific histone N-methyltransferase 2A and promotes transcription by inducing an open chromatin conformation. Numerous genomic breakpoints within the gene have been reported in young children and adults with hematologic disorders and are present in up to 10% of acute leukemias. These rearrangements describe distinct features and worse prognosis depending on the fusion partner, characterized by chemotherapy resistance and high rates of relapse, with a progression-free survival of 30-40% and overall survival below 25%.

Comprehensive Analyses of the Effects of the Small-Molecule Inhibitor of the UHM Domain in the Splicing Factor in Leukemia Cells.

Mutations in RNA splicing factor genes including , , and have been reported to contribute to development of myeloid neoplasms including myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML). Chemical tools targeting cells carrying these mutant genes remain limited and underdeveloped. Among the four proteins, mutant U2AF1 (U2AF1) acquires an altered 3' splice site selection preference and co-operates with the wild-type U2AF1 (U2AF1) to change various gene isoform patterns to support MDS cells survival and proliferation.

Thrombosis in Myeloid Malignancies: From CHIP to AML.

The development of myeloid malignancies is a multi-step process starting from pre-malignant stages. Large-scale studies on clonal hematopoiesis of indeterminate potential (CHIP) identified this condition as a risk factor for developing hematologic malignancies, in particular myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In parallel, CHIP was found to confer an enhanced thrombotic risk, in particular for cardiovascular diseases.

Therapy-Related Myeloid Neoplasm: Biology and Mechanistic Aspects of Malignant Progression.

Therapy-related myeloid neoplasms (t-MN) arise after a documented history of chemo/radiotherapy as treatment for an unrelated condition and account for 10-20% of myelodysplastic syndromes and acute myeloid leukemia. T-MN are characterized by a specific genetic signature, aggressive features and dismal prognosis. The nomenclature and the subsets of these conditions have changed frequently over time, and despite the fact that, in the last classification, they lost their autonomous entity status and became disease qualifiers, the recognition of this feature remains of major importance.

The metabolic fuel of paroxysmal nocturnal haemoglobinuria.

Metabolic reprogramming has been investigated in haematological malignancies. To date, a few studies have analysed the metabolic profile of paroxysmal nocturnal haemoglobinuria (PNH). The study by Chen and colleagues sheds light on the involvement of metabolic changes in the proliferation of PNH clones.

Clonal hematopoiesis-derived therapy-related myeloid neoplasms after autologous hematopoietic stem cell transplant for lymphoid and non-lymphoid disorders.

Therapy-related myeloid neoplasms (tMN) are complications of cytotoxic therapies. Risk of tMN is high in recipients of autologous hematopoietic stem cell transplantation (aHSCT). Acquisition of genomic mutations represents a key pathogenic driver but the origins, timing and dynamics, particularly in the context of preexisting or emergent clonal hematopoiesis (CH), have not been sufficiently clarified.

Paroxysmal nocturnal hemoglobinuria-related thrombosis in the era of novel therapies: a 2043-patient-year analysis.

Thrombophilia is one of the principal features of paroxysmal nocturnal hemoglobinuria (PNH) and constitutes the main cause of disease morbidity/mortality. Anticomplement treatment has revolutionized the natural history of PNH, with control of the hemolytic process and abolition of thrombotic events (TEs). However, no guidelines exist for the management of thromboembolic complications in this setting, with type and duration of anticoagulation depending on individual practices.

Capturing the unpredictability of stem cells.

A new mathematical model that can be applied to both single-cell and bulk DNA sequencing data sheds light on the processes governing population dynamics in stem cells.

Clonal hematopoiesis and autoimmunity.

Clonal hematopoiesis (CH) has been associated with aging, occurring in about 10% of individuals aged >70 years, and immune dysfunction. Aged hematopoietic stem and progenitor cells exhibit pathological changes in immune function and activation of inflammatory pathways. CH clones commonly harbor a loss of function mutation in DNMT3A or TET2, which causes increased expression of inflammatory signaling genes, a proposed mechanism connected to CH and the development of age-related diseases.

Molecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting.

PHF6 mutations (PHF6) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Here we show three main findings in our comprehensive genomic and proteomic study.

Splenectomy outcomes in immune cytopenias: Treatment outcomes and determinants of response.

Background: Splenectomy is commonly used to treat refractory immune-mediated cytopenia, but there are no established factors that are associated with response to the procedure.

Objectives: A cohort study was conducted to evaluate the hematologic and surgical outcomes of splenectomy in adult patients with immune cytopenias and identify preoperative factors associated with response.

Methods: Data from the Cleveland Clinic Foundation for 1824 patients aged over 18 who underwent splenectomy from 2002 to 2020 were analyzed.

Immunotherapy in Acute Myeloid Leukemia: A Literature Review of Emerging Strategies.

In the last twenty years, we have witnessed a paradigm shift in the treatment and prognosis of acute myeloid leukemia (AML), thanks to the introduction of new efficient drugs or approaches to refine old therapies, such as Gemtuzumab Ozogamicin, CPX 3-5-1, hypomethylating agents, and Venetoclax, the optimization of conditioning regimens in allogeneic hematopoietic stem cell transplantation and the improvement of supportive care. However, the long-term survival of non-M3 and non-core binding factor-AML is still dismal. For this reason, the expectations for the recently developed immunotherapies, such as antibody-based therapy, checkpoint inhibitors, and chimeric antigen receptor strategies, successfully tested in other hematologic malignancies, were very high.

Paroxysmal Nocturnal Hemoglobinuria: Biology and Treatment.

Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder characterized by the lack of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as a consequence of somatic mutations in the phosphatidylinositol glycan anchor biosynthesis class A () gene. Clinical manifestations of PNH are intravascular hemolysis, thrombophilia, and bone marrow failure. Treatment of PNH mainly relies on the use of complement-targeted therapy (C5 inhibitors), with the newest agents being explored against other factors involved in the complement cascade to alleviate unresolved intravascular hemolysis and extravascular hemolysis.