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Bone Marrow Pathology has been extensively revised to reflect the significant advances which have occurred in the application of cytogenetics and in particular, molecular genetics in the diagnosis, classification and understanding of haematological disorders. This comprehensive book not only provides information on all common disease entities, but also covers rare disorders in which bone marrow examination is useful. It is designed as a practical resource with \"problems and pitfalls\" highlighted throughout to aid laboratory diagnosis.

ZBTB7A is frequently mutated in acute myeloid leukemia (AML) with t(8;21) translocation. However, the oncogenic collaboration between mutated ZBTB7A and the RUNX1–RUNX1T1 fusion gene in AML t(8;21) remains unclear. Here, we investigate the role of ZBTB7A and its mutations in the context of normal and malignant hematopoiesis. We demonstrate that clinically relevant ZBTB7A mutations in AML t(8;21) lead to loss of function and result in perturbed myeloid differentiation with block of the granulocytic lineage in favor of monocytic commitment. In addition, loss of ZBTB7A increases glycolysis and hence sensitizes leukemic blasts to metabolic inhibition with 2-deoxy-d-glucose. We observed that ectopic expression of wild-type ZBTB7A prevents RUNX1-RUNX1T1-mediated clonal expansion of human CD34+ cells, whereas the outgrowth of progenitors is enabled by ZBTB7A mutation. Finally, ZBTB7A expression in t(8;21) cells lead to a cell cycle arrest that could be mimicked by inhibition of glycolysis. Our findings suggest that loss of ZBTB7A may facilitate the onset of AML t(8;21), and that RUNX1-RUNX1T1-rearranged leukemia might be treated with glycolytic inhibitors.

Acute myeloid leukaemia (AML) is distinguished by the generation of dysfunctional leukaemic blasts, and patients characteristically suffer from fatal infections and anaemia due to insufficient normal myelo-erythropoiesis. Direct physical crowding of bone marrow (BM) by accumulating leukaemic cells does not fully account for this haematopoietic failure. Here, analyses from AML patients were applied to both in vitro co-culture platforms and in vivo xenograft modelling, revealing that human AML disease specifically disrupts the adipocytic niche in BM. Leukaemic suppression of BM adipocytes led to imbalanced regulation of endogenous haematopoietic stem and progenitor cells, resulting in impaired myelo-erythroid maturation. In vivo administration of PPARγ agonists induced BM adipogenesis, which rescued healthy haematopoietic maturation while repressing leukaemic growth. Our study identifies a previously unappreciated axis between BM adipogenesis and normal myelo-erythroid maturation that is therapeutically accessible to improve symptoms of BM failure in AML via non-cell autonomous targeting of the niche. Boyd et al. monitored the effects of patient-derived acute myeloid leukaemia (AML) cells on human HSPCs in vivo and found that AML impairs bone marrow adipocyte differentiation, and this in turn impedes healthy endogenous haematopoiesis.

Bone marrow lesions (BMLs) around the knee are a common magnetic resonance imaging (MRI) finding. However, despite the growing interest on BMLs in multiple pathological conditions, they remain controversial not only for the still unknown role in the etiopathological processes, but also in terms of clinical impact and treatment. The differential diagnosis includes a wide range of conditions: traumatic contusion and fractures, cyst formation and erosions, hematopoietic and infiltrated marrow, developmental chondroses, disuse and overuse, transient bone marrow oedema syndrome and, lastly, subchondral insufficiency fractures and true osteonecrosis. Regardless the heterogeneous spectrum of these pathologies, a key factor for patient management is the distinction between reversible and irreversible conditions. To this regard, MRI plays a major role, leading to the correct diagnosis based on recognizable typical patterns that have to be considered together with coexistent abnormalities, age, and clinical history. Several treatment options have been proposed, from conservative to surgical approaches. In this manuscript the main lesion patterns and their management have been analysed to provide the most updated evidence for the differential diagnosis and the most effective treatment. Level of evidence IV.

Objective Braces used to treat (PF) osteoarthritis (OA) may reduce contact stress across the PF joint. We hypothesised that in PF OA, braces would decrease knee pain and shrink PF bone marrow lesions (BMLs). Methods Eligible subjects had painful PF OA. Subjects were randomly allocated to brace or no brace for 6 weeks. Knee MRIs were acquired at baseline and 6 weeks. We measured BMLs on post-contrast fat suppressed sagittal and proton density weighted axial images. The primary symptom outcome was change in pain at 6 weeks during a preselected painful activity, and the primary structural outcome was BML volume change in the PF joint. Analyses used multiple linear regression. Results We randomised 126 subjects aged 40–70 years (mean age 55.5  years; 72 females (57.1%)). Mean nominated visual analogue scale (0–10 cm) pain score at baseline was 6.5 cm. 94 knees (75%) had PF BMLs at baseline. Subjects wore the brace for a mean of 7.4 h/day. 6 subjects withdrew during the trial. After accounting for baseline values, the brace group had lower knee pain than the control group at 6 weeks (difference between groups −1.3 cm, 95% CI −2.0 to −0.7; p<0.001) and reduced PF BML volume (difference −490.6 mm3, 95% CI −929.5 to −51.7; p=0.03) but not tibiofemoral volume (difference −53.9 mm3, 95% CI −625.9 to 518.2; p=0.85). Conclusions A PF brace reduces BML volume in the targeted compartment of the knee, and relieves knee pain. Trial registration number UK. ISRCTN50380458.

Background Subchondral bone changes, which include bone marrow lesion (BML), subchondral bone attrition (SBA) and subchondral bone cyst (SBC) by magnetic resonance imaging (MRI) analysis, are reportedly implicated for knee pain in knee osteoarthritis (OA). However, the relationship between these subchondral bone changes and OA knee pain and the effect of articular cartilage lesion on the pain remain elusive. Methods Elderly subjects (1,145 subjects, 72.9 years old on average) in the Bunkyo Health Study, 71.5% of whom had knee OA with ≥ Kellgren-Lawrence grade 2, were enrolled. Knee pain in daily life over the past few days was measured using Visual Analogue Scale (VAS) in the Japanese Knee Osteoarthritis Measure. The subjects without or with pain were defined if they indicated a pain VAS score of 0 or a pain VAS score of ≥ 1. The association was examined between knee pain and MRI-detected OA structural changes which were determined according to the Whole Organ Magnetic Resonance Imaging Score. Results While 62.2% of the subjects were free from knee pain, 37.8% of the subjects had knee pain. Knee pain was not related with cartilage lesion without subchondral bone changes (odds ratio [OR]: 1.10 [95% confidence interval [CI]: 0.83–1.46]) or BML alone (OR: 1.32 [95% CI: 0.95–1.83]). However, knee pain was significantly associated with BML coexistent with SBA (OR: 2.22 [95% CI: 1.25–3.97]), SBC (OR: 1.79 [95% CI: 1.28–2.51]), or both SBA and SBC (OR: 2.18 [95% CI: 1.35–3.53]). Similar positive relationships between knee pain and coexisted subchondral bone changes were obtained regardless of the presence or absence of cartilage lesion present above the BML region. When BML was not coexistent with either SBA or SBC regardless of cartilage lesion above the subchondral bone changes, BML was not associated with knee pain (OR: 1.26 [95% CI: 0.90–1.77]) or (OR: 2.16 [95% CI: 0.89–5.23]). Conclusions BML coexistent with SBA and/or SBC, but not BML without the coexistence, was associated with knee pain in the elderly with knee OA regardless of the presence or absence of cartilage lesion.

Objectives: To determine the effect of iterative refinement of standard ordering protocols on test utilization and results for bone marrow biopsy specimens. Methods: Eighteen months of test utilization and result data were used to revise the protocols that determine cytogenetic and molecular test selection on bone marrow specimens and then compared with data obtained following protocol revision. Results: Revision of protocols resulted in reduction in total tests and associated charges, due to a decrease in tests both concordant and discordant with the protocols. These reductions only occurred in diseases for which revisions were made and were limited to cases in which reflex testing was performed. There was an increase in the fraction of positive tests, which was also limited to reflex testing. Conclusions: Data-driven iterative revision of protocols further improves test utilization and performance, while reducing cost. Analysis of testing data can be used to continuously improve test ordering decisions.

Metastasis is the major cause of cancer-related deaths. Neuroblastoma (NB), a childhood tumor has been molecularly defined at the primary cancer site, however, the bone marrow (BM) as the metastatic niche of NB is poorly characterized. Here we perform single-cell transcriptomic and epigenomic profiling of BM aspirates from 11 subjects spanning three major NB subtypes and compare these to five age-matched and metastasis-free BM, followed by in-depth single cell analyses of tissue diversity and cell-cell interactions, as well as functional validation. We show that cellular plasticity of NB tumor cells is conserved upon metastasis and tumor cell type composition is NB subtype-dependent. NB cells signal to the BM microenvironment, rewiring via macrophage mgration inhibitory factor and midkine signaling specifically monocytes, which exhibit M1 and M2 features, are marked by activation of pro- and anti-inflammatory programs, and express tumor-promoting factors, reminiscent of tumor-associated macrophages. The interactions and pathways characterized in our study provide the basis for therapeutic approaches that target tumor-to-microenvironment interactions. The bone marrow is a common site of metastasis for neuroblastoma patients. Here, the authors perform single cell RNA-seq and ATAC-seq of bone marrow aspirates from 16 subjects and show conservation of tumor cell plasticity in metastases and identify tumor-to-bone marrow cell signals that trigger tumor promoting monocytes.

Bone marrow mesenchymal stromal cells (MSCs) constitute one of the important components of the hematopoietic microenvironmental niche. In vivo studies have shown that depletion of marrow MSCs resulted in reduction of hematopoietic stem cell content, and there is in vitro evidence that marrow MSCs are able to support leukemia progenitor cell proliferation and survival and provide resistance to cytotoxic therapies. How MSCs from leukemia marrow differ from normal counterparts and how they are influenced by the presence of leukemia stem and progenitor cells are still incompletely understood. In this work, we compared normal donor (ND) and acute myelogenous leukemia (AML) derived MSCs and found that AML-MSCs had increased adipogenic potential with improved ability to support survival of leukemia progenitor cells. To identify underlying changes, RNA-Seq analysis was performed. Gene ontology and pathway analysis revealed adipogenesis to be among the set of altered biological pathways dysregulated in AML-MSCs as compared with ND-MSCs. Expression of both SOX9 and EGR2 was decreased in AML-MSCs as compared with ND-MSCs. Increasing expression of SOX9 decreased adipogenic potential of AML-MSCs and decreased their ability to support AML progenitor cells. These findings suggest that AML-MSCs possess adipogenic potential which may enhance support of leukemia progenitor cells.

ObjectiveIdentify factors associated with presence and extension of spinal and sacroiliac joints (SIJ)–MRI lesions suggestive of axial spondyloarthritis (axSpA) in a population-based cohort (Study of Health in Pomerania) aged <45 years.MethodsSpinal (sagittal T1/T2) and SIJ (semicoronal STIR sequences) MRIs were evaluated by two trained blinded readers. The presence (yes/no) and extension (Berlin MRI Score) of bone marrow oedema (BME) were captured. Degenerative spinal lesions were excluded and discrepancies resolved by consensus. Cross-sectional associations between clinical factors and presence/extension of BME were analysed by logistic/negative binomial regression. Record linkage of claims data was applied to identify participants with axSpA.ResultsMRIs of 793 volunteers were evaluated. The presence of SIJ–BME (odds ratio) was strongly associated delivery during the last year (4.47, 1.49–13.41). For SIJ–BME extension, associations (incidence rate ratios, 95% CI) were found for delivery ((during last year) 4.52, 1.48–13.84), human leucocyte antigen (HLA)-B27+ (2.32, 1.30–4.14), body mass index (25–30 vs <25 kg/m²; 1.86 (1.19–2.89)) and back pain ((last 3 months) 1.55, 1.04–2.31), while for spinal BME, associations were found for age per decade (1.46, 1.13–1.90) and physically demanding work (1.46, 1.06–2.00). Record linkage was available for 694 (87.5%) participants and 9/694 (1.3%) had a record of axSpA (ICD M45.09).ConclusionThese population-based data support the hypothesis of mechanic strain contributing to BME in the general population aged <45 years and the role of HLA-B27+ as a severity rather than a susceptibility factor for SIJ–BME.