Clinical and molecular characterization of TP53-mutant acute lymphoblastic leukemia in adults.

TP53-mutant acute lymphoblastic leukemia (ALL) in adults is a high-risk subtype with poor outcomes, yet its molecular landscape and clinical implications remain incompletely defined. In this multi-institutional study of 830 adult ALL patients treated at eight academic centers between 2010 and 2024, we demonstrated that TP53 mutations are independent predictors of inferior overall survival in both B-ALL (median, 1.9 vs 5 years) and T-ALL (1.

ANKRD26-related thrombocytopenia 2 with a baseline increase in blasts: implications for clinical surveillance.

We report on 8 patients with ankyrin repeat domain 26 (ANKRD26)-related thrombocytopenia 2 (ANKRD26-RT) with elevated bone marrow myeloblasts and dysmegakaryopoiesis, without somatic genetic abnormalities or progression to malignancy during long-term observation, findings which may constitute inherent ANKRD26-RT biology rather than progression to myeloid malignancy.

Overall cancer risk in people with deleterious germline variants.

Germline loss-of-function (LoF) DDX41 variants predispose to late-onset hematopoietic malignancies (HM), predominantly of myeloid lineage. Among 43 families with germline DDX41LoF variants, bone marrow (BM) biopsies in those without (N=8) or with malignancies (N=21) revealed mild dysplasia in peripheral blood (57%) and BM (88%), long before the average age of DDX41-related HM onset. Therefore, we recommend baseline BM biopsies in people with germline DDX41LoF alleles to avoid over-diagnosis of myelodysplastic syndromes.

Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms.

Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24).

Socioeconomic determinants of the biology and outcomes of acute lymphoblastic leukemia in adults.

Various socioeconomic and biologic factors affect cancer health disparities and differences in health outcomes. To better characterize the socioeconomic vs biologic determinants of acute lymphoblastic leukemia (ALL) outcomes, we conducted a single-institution, retrospective analysis of adult patients with ALL treated at the University of Chicago (UChicago) from 2010 to 2022 and compared our outcomes with the US national data (the Surveillance, Epidemiology, and End Results [SEER] database). Among 221 adult patients with ALL treated at UChicago, BCR::ABL1 was more frequent in patients with higher body mass index (BMI; odds ratio [OR], 7.

Ozanimod-exposed Patients with Ulcerative Colitis Undergoing Total Colectomy Exhibit Unique Lymph Node Histological Changes.

Introduction: Ozanimod regulates lymphocyte egress from the spleen and lymph nodes into the systemic circulation. The histological changes which occur in the lymph nodes of patients on ozanimod is unknown.

Materials And Methods: This retrospective study included patients with ulcerative colitis [UC] undergoing total colectomy for treatment-refractory disease who received ozanimod, and a cohort of patients with UC undergoing colectomy who did not have ozanimod exposure.

GLUT1 Immunohistochemistry Is a Highly Sensitive and Relatively Specific Marker for Erythroid Lineage in Benign and Malignant Hematopoietic Tissues.

Objectives: Glucose transporter 1 (GLUT1), a glucose transporter, is an abundant protein in erythrocytes with expression beginning early in erythropoiesis. We sought to evaluate the utility of GLUT1 immunohistochemistry (IHC) as a diagnostic marker for identifying erythroid differentiation in hematopoietic tissues, including neoplastic erythroid proliferations.

Methods: A variety of benign and neoplastic bone marrow biopsy specimens containing variable proportions of erythroid precursors were selected (n = 46, including 36 cases of leukemia).

RNA Epigenetics: Fine-Tuning Chromatin Plasticity and Transcriptional Regulation, and the Implications in Human Diseases.

Chromatin structure plays an essential role in eukaryotic gene expression and cell identity. Traditionally, DNA and histone modifications have been the focus of chromatin regulation; however, recent molecular and imaging studies have revealed an intimate connection between RNA epigenetics and chromatin structure. Accumulating evidence suggests that RNA serves as the interplay between chromatin and the transcription and splicing machineries within the cell.

OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia.

Internal tandem duplication (-ITD) mutations of Fms-like tyrosine kinase 3 (FLT3) provide growth and pro-survival signals in the context of established driver mutations in FLT3 mutant acute myeloid leukemia (AML). Maternal embryonic leucine zipper kinase (MELK) is an aberrantly expressed gene identified as a target in AML. The MELK inhibitor OTS167 induces cell death in AML including cells with FLT3 mutations, yet the role of MELK and mechanisms of OTS167 function are not understood.

The Role of RNA Modifications and RNA-modifying Proteins in Cancer Therapy and Drug Resistance.

The advent of new genome-wide sequencing technologies has uncovered abnormal RNA modifications and RNA editing in a variety of human cancers. The discovery of reversible RNA N6-methyladenosine (RNA: mA) by fat mass and obesity-associated protein (FTO) demethylase has led to exponential publications on the pathophysiological functions of mA and its corresponding RNA modifying proteins (RMPs) in the past decade. Some excellent reviews have summarized the recent progress in this field.

Cytotoxic Therapy-Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms.

Therapy-related myeloid neoplasms (t-MNs) following treatment with alkylating agents are characterized by a del(5q), complex karyotypes, alterations of and a dismal prognosis. To decipher the molecular pathway(s) leading to the pathogenesis of del(5q) t-MN and the effect(s) of cytotoxic therapy on the marrow microenvironment, we developed a mouse model with loss of two key del(5q) genes, and , in hematopoietic cells. We used the well-characterized drug, N-ethyl-N-nitrosurea (ENU) to demonstrate that alkylating agent exposure of stromal cells in the microenvironment increases the incidence of myeloid disease.

Periplasmic Protein EipB Is a Molecular Determinant of Cell Envelope Integrity and Virulence.

The Gram-negative cell envelope is a remarkable structure with core components that include an inner membrane, an outer membrane, and a peptidoglycan layer in the periplasmic space between. Multiple molecular systems function to maintain integrity of this essential barrier between the interior of the cell and its surrounding environment. We show that a conserved DUF1849 family protein, EipB, is secreted to the periplasmic space of species, a monophyletic group of intracellular pathogens.

Periplasmic protein EipA determines envelope stress resistance and virulence in Brucella abortus.

Molecular components of the Brucella abortus cell envelope play a major role in its ability to infect, colonize and survive inside mammalian host cells. In this study, we have defined a role for a conserved gene of unknown function in B. abortus envelope stress resistance and infection.

Severe hemophagocytic lymphohistiocytosis in a melanoma patient treated with ipilimumab + nivolumab.

Background: Treatment of metastatic melanoma patients with immune checkpoint inhibitors is an important standard of care. Side effects are due to immune activation, can affect virtually all organ systems, and are occasionally severe. Although hematologic toxicity has been reported, we present a case of hemophagocytic lymphohistiocytosis (HLH) due to immune checkpoint inhibitor therapy.

Author Correction: RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia.

In the originally published version of this Article, the GAPDH loading control blot in Fig. 1a was inadvertently replaced with a duplicate of the DNMT2 blot in the same panel during assembly of the figure. This has now been corrected in both the PDF and HTML versions of the Article.

RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia.

The roles of RNA 5-methylcytosine (RNA:mC) and RNA:mC methyltransferases (RCMTs) in lineage-associated chromatin organization and drug response/resistance are unclear. Here we demonstrate that the RCMTs, namely NSUN3 and DNMT2, directly bind hnRNPK, a conserved RNA-binding protein. hnRNPK interacts with the lineage-determining transcription factors (TFs), GATA1 and SPI1/PU.

A Herald of Plasma Cell Myeloma: A Report of Malignant Plasma Cells Identified in Parathyroid Adenoma and a Review of Non-parathyroid Malignancies in Parathyroid Glands.

Involvement of the parathyroid glands by non-parathyroid neoplasia is an infrequent event. Rare cases of metastases to the parathyroid gland have been reported in parathyroidectomies and autopsies of patients with known solid or hematopoietic malignancies. Here, we present a case of atypical clonal plasma cells incidentally identified within a parathyroid adenoma resected for hyperparathyroidism and hypercalcemia, which served as the sentinel event for a subsequent diagnosis of plasma cell myeloma.

Inhibition of WNT signaling in the bone marrow niche prevents the development of MDS in the MDS mouse model.

There is accumulating evidence that functional alteration(s) of the bone marrow (BM) microenvironment contribute to the development of some myeloid disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition to a cell-intrinsic role of WNT activation in leukemia stem cells, WNT activation in the BM niche is also thought to contribute to the pathogenesis of MDS and AML. We previously showed that the -haploinsufficient mice ( ) model MDS induced by an aberrant BM microenvironment.

Brucella abortus ΔrpoE1 confers protective immunity against wild type challenge in a mouse model of brucellosis.

The Brucella abortus general stress response (GSR) system regulates activity of the alternative sigma factor, σ(E1), which controls transcription of approximately 100 genes and is required for persistence in a BALB/c mouse chronic infection model. We evaluated the host response to infection by a B. abortus strain lacking σ(E1) (ΔrpoE1), and identified pathological and immunological features that distinguish ΔrpoE1-infected mice from wild-type (WT), and that correspond with clearance of ΔrpoE1 from the host.

MDI 301 suppresses myeloid leukemia cell growth in vitro and in vivo without the toxicity associated with all-trans retinoic acid therapy.

MDI 301 is a novel 9-cis retinoic acid derivative in which the terminal carboxylic acid group has been replaced by a picolinate ester. MDI 301, a retinoic acid receptor-α - agonist, suppressed the growth of several human myeloid leukemia cell lines (HL60, NB4, OCI-M2, and K562) in vitro and induced cell-substrate adhesion in conjunction with upregulation of CD11b. Tumor growth in HL60-injected athymic nude mice was reduced.

Indolent T-cell lymphoproliferative disease of the gastrointestinal tract.

Primary gastrointestinal (GI) T-cell lymphoma is an infrequent and aggressive disease. However, rare indolent clonal T-cell proliferations in the GI tract have been described. We report 10 cases of GI involvement by an indolent T-cell lymphoproliferative disease, including 6 men and 4 women with a median age of 48 years (range, 15-77 years).

Orbital myeloid sarcoma in an adult with acute myeloid leukemia, FAB M1, and 12p-deletion.

A 49-year-old woman with acute myeloid leukemia, FAB M1 subtype, and 12p deletion, presented with progressive right proptosis and diplopia for 1 week. Orbital CT revealed a homogenously enhancing, orbital mass engulfing the inferior rectus muscle. Histopathology revealed myeloid sarcoma for which she underwent external beam radiotherapy.

Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities.

Genome-scale studies have revealed extensive, cell type-specific colocalization of transcription factors, but the mechanisms underlying this phenomenon remain poorly understood. Here, we demonstrate in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions.

A recurrent network involving the transcription factors PU.1 and Gfi1 orchestrates innate and adaptive immune cell fates.

The transcription factor PU.1, encoded by the Sfpi1 gene, functions in a graded manner to regulate macrophage versus B cell generation; its higher concentration favors the macrophage fate. We demonstrated that Gfi1 reciprocally promoted B cell fate choice at the expense of myeloid progeny.