Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort.

The World Health Organization (WHO-5) and International Consensus Classification (ICC) acknowledge the poor prognosis of TP53-mutated (TP53) myeloid neoplasm (MN). However, there are substantial differences between the two classifications that may lead to under- or overestimation of the prognostic risk. We retrospectively applied WHO-5 and ICC to 603 MN cases harboring TP53 (variant allele frequency, VAF ≥ 2%).

Evidence-based risk stratification of myeloid neoplasms harboring TP53 mutations.

This retrospective analysis aimed to provide evidence-based risk stratification of TP53-mutated (TP53mut) myeloid neoplasms (MNs). Of 580 MNs harboring TP53mut with variant allele frequency (VAF) ≥2%, 219 (37.8%), 194 (33.

Haploinsufficiency of miR-143 and miR-145 reveal targetable dependencies in resistant del(5q) myelodysplastic neoplasm.

Myelodysplastic neoplasms (MDS) are stem cell disorders characterized by ineffective hematopoiesis and risk of transformation to acute myeloid leukemia (AML). Chromosomal alterations are frequent in MDS, with interstitial deletion of chromosome 5q (del(5q)) being the most common. Lenalidomide is the current first-line treatment for del(5q) MDS and its efficacy relies on degradation of CK1α which is encoded by the CSNK1A1 gene located in the commonly deleted region (CDR) of chromosome 5q.

Case report: Rare case of donor cell-derived T-cell acute lymphoblastic leukaemia in a female patient after receiving an allo-transplant from her male sibling.

Donor-derived haematological neoplasms, in which recipients present with haematological malignancies that have evolved from transplant donor stem cells, have previously been described for myelodysplastic syndrome, myeloproliferative neoplasms, acute myeloid leukaemia and less often, leukaemias of lymphoid origin. Here we describe a rare and complex case of donor-derived T-cell acute lymphoblastic leukaemia with a relatively short disease latency of less than 4 years. Through genomic and in vitro analyses, we identified novel mutations in NOTCH1 as well as a novel activating mutation in STAT5B; the latter targetable with the clinically available drugs, venetoclax and ruxolitinib.

Solute Carrier Family 29A1 Mediates In Vitro Resistance to Azacitidine in Acute Myeloid Leukemia Cell Lines.

Azacitidine (AZA) is commonly used hypomethylating agent for higher risk myelodysplastic syndromes and acute myeloid leukemia (AML). Although some patients achieve remission, eventually most patients fail AZA therapy. Comprehensive analysis of intracellular uptake and retention (IUR) of carbon-labeled AZA (C-AZA), gene expression, transporter pump activity with or without inhibitors, and cytotoxicity in naïve and resistant cell lines provided insight into the mechanism of AZA resistance.

A senescence stress secretome is a hallmark of therapy-related myeloid neoplasm stromal tissue occurring soon after cytotoxic exposure.

Therapy-related myeloid neoplasm (tMN) is considered a direct consequence of DNA damage in hematopoietic stem cells. Despite increasing recognition that altered stroma can also drive leukemogenesis, the functional biology of the tMN microenvironment remains unknown. We performed multiomic (transcriptome, DNA damage response, cytokine secretome and functional profiling) characterization of bone marrow stromal cells from tMN patients.

Targeted gene panels identify a high frequency of pathogenic germline variants in patients diagnosed with a hematological malignancy and at least one other independent cancer.

The majority of studies assessing the contribution of pathogenic germline variants (PGVs) to cancer predisposition have focused on patients with single cancers. We analyzed 45 known cancer predisposition genes (CPGs) in germline samples of 202 patients with hematological malignancies (HMs) plus one or more other independent cancer managed at major tertiary medical centers on two different continents. This included 120 patients with therapy-related myeloid neoplasms (t-MNs), where the HM occurred after cytotoxic treatment for a first malignancy, and 82 patients with multiple cancers in which the HM was not preceded by cytotoxic therapy (MC-HM).

The mutational burden of therapy-related myeloid neoplasms is similar to primary myelodysplastic syndrome but has a distinctive distribution.

Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct.

Red cell alloimmunization is associated with development of autoantibodies and increased red cell transfusion requirements in myelodysplastic syndrome.

Up to 90% of patients with a myelodysplastic syndrome require red blood cell transfusion; nevertheless, comprehensive data on red cell alloimmunization in such patients are limited. This study evaluates the incidence and clinical impact of red cell alloimmunization in a large cohort of patients with myelodysplastic syndrome registered in the statewide South Australian-MDS registry. The median age of the 817 patients studied was 73 years, and 66% were male.

Dynamic assessment of RBC-transfusion dependency improves the prognostic value of the revised-IPSS in MDS patients.

RBC-transfusion dependency (RBC-TD) is an independent prognostic factor for poor overall survival (OS) in the WHO classification-based prognostic scoring system (WPSS) for MDS patients. However, WPSS did not include cytopenia, whereas revised International Prognostic Scoring System (IPSS-R) did not include RBC-TD. Thus, neither of these prognostic scoring systems incorporates both cytopenia and RBC-TD.