Acute myeloid leukaemia in its niche: the bone marrow microenvironment in acute myeloid leukaemia

Purpose of Review Acute myeloid leukaemia (AML) is a heterogeneous malignancy for which treatment options remain suboptimal. It is clear that a greater understanding of the biology of the AML niche will enable new therapeutic strategies to be developed in order to improve treatment outcomes for patients. Recent Findings Recent evidence has highlighted the importance of the bone marrow microenvironment in protecting leukaemia cells, and in particular leukaemic stem cells from chemotherapy-induced cell death. This includes mesenchymal stem cells supporting growth and preventing apoptosis, and altered action and secretion profiles of other niche components including adipocytes, endothelial cells and T cells. Summary Here, we provide a detailed overview of the current understanding of the AML bone marrow microenvironment. Clinical trials of agents that mobilise leukaemic stem cells from the bone marrow are currently ongoing and show early promise. Future challenges will involve combining these novel therapies targeted at the AML niche with conventional chemotherapy treatment

Boron excess imbalances root/shoot allometry, photosynthetic and chlorophyll fluorescence parameters and sugar metabolism in apple plants

Boron (B) excess frequently impair plant performances and their productivity; in particular in arid and semi‐arid environments. In the present experiment; hydroponically‐grown ‘Granny Smith’ apple plants grafted on M9 rootstock were treated with optimal (25 μΜ) or excess (400 μΜ) B for 116 days to evaluate allometric responses of plants to B toxicity and to highlight physiological (photosynthesis and chlorophyll fluorescence) and biochemical (pigment content and sugar metabolism) responses of apple plants to B excess. Boron accumulated principally in top > middle > basal stems and leaves of high‐B‐stressed plants. Notably, the stem dramatically accumulated a higher level of B, as an attempt to preserve leaves, especially the youngest from further B accumulation. B accumulation seriously affected photosynthesis of younger leaves and caused both stomata (reduced stomatal conductance) and biochemical (reduction of apparent CO2 use efficiency and pigment content) limitations and altered the photochemistry and energy partitioning in photosystem II. Boron excess altered leaf sugar proportion; increasing the accumulation of non‐translocating sugars such as glucose and fructose. Our dataset adds knowledge on the effect of B excess in apple tree and poses serious concerns about the possible effect of B in altering sugar metabolism; which, in turn, can strongly affect fruit production of this worldwide‐cropped species

Acute leukaemia: no reason to panic

Acute leukaemia is characterised by uncontrolled expansion of immature leukocytes, either myeloid or lymphoid progenitors, leading to acute myeloid leukaemia (AML) and acute lymphoid leukaemia (ALL), respectively. If left untreated, it is life-threatening and can lead to death within weeks. When acute leukaemia is suspected, urgent haematology input should be sought. Appropriate investigations are needed promptly to confirm diagnosis and start treatment. A multidisciplinary approach is vital to ensure appropriate management

Dissecting the role of the CXCL12/CXCR4 axis in acute myeloid leukaemia

Acute myeloid leukaemia (AML) is the most common adult acute leukaemia with the lowest survival rate. It is characterised by a build‐up of immature myeloid cells anchored in the protective niche of the bone marrow (BM) microenvironment. The CXCL12/CXCR4 axis is central to the pathogenesis of AML as it has fundamental control over AML cell adhesion into the protective BM niche, adaptation to the hypoxic environment, cellular migration and survival. High levels of CXCR4 expression are associated with poor relapse‐free and overall survival. The CXCR4 ligand, CXCL12 (SDF‐1), is expressed by multiple cells types in the BM, facilitating the adhesion and survival of the malignant clone. Blocking the CXCL12/CXCR4 axis is an attractive therapeutic strategy providing a ‘multi‐hit’ therapy that both prevents essential survival signals and releases the AML cells from the BM into the circulation. Once out of the protective niche of the BM they would be more susceptible to destruction by conventional chemotherapeutic drugs. In this review, we disentangle the diverse roles of the CXCL12/CXCR4 axis in AML. We then describe multiple CXCR4 inhibitors, including small molecules, peptides, or monoclonal antibodies, which have been developed to date and their progress in pre‐clinical and clinical trials. Finally, the review leads us to the conclusion that there is a need for further investigation into the development of a ‘multi‐hit’ therapy that targets several signalling pathways related to AML cell adhesion and maintenance in the BM

Lymphocytosis and chronic lymphocytic leukaemia: investigation and management

Lymphocytosis is a common blood-test finding. Establishing whether the cause of lymphocytosis is benign or malignant is key to managing patients appropriately. A lymphocytosis should always prompt clinical review including a thorough history, examination and appropriate preliminary investigations (blood tests, blood film). The majority of patients with chronic lymphocytic leukaemia (CLL) present incidentally due to a lymphocytosis found on routine blood tests. Patient outcomes vary considerably based on genetic pre-disposition and various prognostic markers (age, Binet or Rai staging, and B2-microglobulin). Although not curative, chemo-immunotherapy is an effective treatment strategy for the majority of CLL patients with progressive disease. More recently, novel oral therapies have been developed that target key signalling and apoptosis pathways and that are being used in relapse settings and as first-line treatments for certain patients

PS1424 The CRAB score: a simple prognostic tool in multiple myeloma

Background: Current prognostic scoring systems in multiple myeloma lack consensus and are often clinically impractical. The key diagnostic features known as CRAB; hypercalcaemia (C), renal impairment (R), anaemia (A), and bone lesions (B), are known to represent end organ damage in myeloma. Aims: We aimed to produce a simplified and practical prognostic tool for use in multiple myeloma patients as an alternative to current practice, therefore enabling prognostic guidance to be distributed to a wider group of patients. Since the laboratory tests required to calculate CRAB score are routinely undertaken in clinical practice, we proposed a method of predicting outcome based on these results alone, which has not yet been reported. Methods: We examined a combined database of clinical and survival information for 314 patients from Brighton and Worthing, Sussex, UK, over a 6 year period, who were newly diagnosed with myeloma, and represent real-world clinical experience. To determine the presence of a CRAB feature, the cut-off values previously defined by the International Myeloma Working Group (IMWG) were used; serum calcium >2·75 mmol/L, serum creatinine >177 μmol/L, haemoglobin 20 g/L below lower limit of normal), and one or more osteolytic lesion on skeletal radiography, CT, PET-CT or MRI. Patients were stratified into five CRAB score groups by having either 0, 1, 2, 3 or 4 CRAB features at initial presentation, with a score of 0 denoting a diagnosis of smouldering myeloma. We then studied the relationship between CRAB score and overall survival using Kaplan Meier curves plotted by the statistics programme SPSS. Results: Our analysis reveals that each additional CRAB feature confers a stepwise statistically significant poorer outcome in terms of overall survival as shown in Figure 1a. This result was regardless of the treatment regimen the patient received and gave 5-year survival percentages of 81%, 58%, 41%, 22% and 0% for patients with CRAB scores 0–4 respectively. We also found CRAB score to have coherence with the current International Staging System (ISS) scoring system, which combines serum albumin as a measure of general patient health with β2-microglobulin as a measure of tumour bulk to estimate risk. Cytogenetic data required for the revised ISS score was not undertaken for the majority of patients, highlighting the lack of feasibility of this system in practice, although we did observe higher CRAB scores for those patients identified with poor risk chromosomal abnormalities. A trend for higher ISS score with higher CRAB score was observed, further validating the CRAB scoring system (figure 1b). Image Summary/Conclusion: Our study shows that the CRAB score yields accurate prognostic predictions for patients with newly diagnosed multiple myeloma based on simple clinical criteria. It has more prognostic categories than the currently used ISS score (5 versus 3) and superior clinical utility than expensive and time-consuming cytogenetic-based scoring systems that have been recently described. These results indicate that the CRAB score may provide a useful and reliable tool to guide prognostic evaluation in newly diagnosed myeloma patients, requiring only routine laboratory testing to be undertaken, and therefore greater availability to patients in diverse clinical settings

Thrombotic risk in COVID-19: a case series and case-control study

Background: A possible association between COVID-19 infection and thrombosis, either as a direct consequence of the virus or as a complication of inflammation, is emerging in the literature. Data on the incidence of venous thromboembolism (VTE) is extremely limited. Methods: We describe 3 cases of thromboembolism refractory to heparin treatment, the incidence of VTE in an inpatient cohort, and a case-control study to identify risk factors associated with VTE. Results: We identified 274 confirmed (208) or probable (66) COVID-19 patients. 21 (7.7%) were diagnosed with VTE. D-dimer was elevated in both cases (confirmed VTE) and controls (no confirmed VTE) but higher levels were seen in confirmed VTE cases (4.1vs 1.2 µg/mL P <0.001). Conclusion: Incidence of VTE is high in patients hospitalised with COVID-19. Urgent clinical trials are needed to evaluate the role of anticoagulation in COVID-19. Monitoring of D-dimer and anti-factor Xa levels may be beneficial in guiding management

Elucidation of focal adhesion kinase as a modulator of migration and invasion and as a potential therapeutic target in chronic lymphocytic leukemia

The retention and re-migration of Chronic Lymphocytic Leukemia cells into cytoprotective and proliferative lymphoid niches is thought to contribute to the development of resistance, leading to subsequent disease relapse. The aim of this study was to elucidate the molecular processes that govern CLL cell migration to elicit a more complete inhibition of tumor cell migration. We compared the phenotypic and transcriptional changes induced in CLL cells using two distinct models designed to recapitulate the peripheral circulation, CLL cell migration across an endothelial barrier, and the lymph node interaction between CLL cells and activated T cells. Initially, CLL cells were co-cultured with CD40L-expressing fibroblasts and exhibited an activated B-cell phenotype, and their transcriptional signatures demonstrated the upregulation of pro-survival and anti-apoptotic genes and overrepresentation of the NF-κB signaling pathway. Using our dynamic circulating model, we were able to study the transcriptomics and miRNomics associated with CLL migration. More than 3000 genes were altered when CLL cells underwent transendothelial migration, with an overrepresentation of adhesion and cell migration gene sets. From this analysis, an upregulation of the FAK signaling pathway was observed. Importantly, PTK2 (FAK) gene expression was significantly upregulated in migrating CLL cells (PTK2 Fold-change = 4.9). Here we demonstrate that TLR9 agonism increased levels of p-FAK (p ≤ 0.05), which could be prevented by pharmacological inhibition of FAK with defactinib (p ≤ 0.01). Furthermore, a reduction in CLL cell migration and invasion was observed when FAK was inhibited (p ≤ 0.0001), supporting a role for FAK in both CLL migration and tissue invasion. When taken together, our data highlights the potential for combining FAK inhibition with current targeted therapies as a more effective treatment regime for CLL

Targeting the non-canonical NF-κB pathway in chronic lymphocytic leukemia and multiple myeloma

In this study, we evaluated an NF-κB inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B-and T-lymphocytes. Basal NF-κB subunit activity was characterized using an enzyme linked immunosorbent assay (ELISA), and the effects of NIK inhibition were then assessed in terms of cytotoxicity and the expression of nuclear NF-κB subunits following monoculture and co-culture with CD40L-expressing fibroblasts, as a model of the lymphoid niche. CW15337 induced a dose-dependent increase in apoptosis, and nuclear expression of the non-canonical NF-κB subunit, p52, was correlated with sensitivity to CW15337 (p = 0.01; r2 = 0.39). Co-culture on CD40L-expressing cells induced both canonical and non-canonical subunit expression in nuclear extracts, which promoted in vitro resistance against fludarabine and ABT-199 (venetoclax) but not CW15337. Furthermore, the combination of CW15337 with fludarabine or ABT-199 showed cytotoxic synergy. Mechanistically, CW15337 caused the selective inhibition of non-canonical NF-κB subunits and the transcriptional repression of BCL2L1, BCL2A1 and MCL1 gene transcription. Taken together, these data suggest that the NIK inhibitor, CW15337, exerts its effects via suppression of the non-canonical NF-κB signaling pathway, which reverses BCL2 family-mediated resistance in the context of CD40L stimulation

The emerging role of estrogen in B cell malignancies

Increasing evidence implicates a role of estrogens in hematological malignancies. We reviewed current knowledge on the emerging role of estrogens and estrogen receptors in normal B-cell function, chronic lymphocytic leukemia, and B-cell lymphoma. Data support that (1) normal human peripheral blood cells (mononuclear cells, total lymphocytes, T as well as B lymphocytes, and NK cells) express both estrogen receptor subtypes (ERα and ERβ), (2) B-cell malignancies express mainly ERβ while selective ERβ agonists inhibit cell growth and induce apoptosis, (3) estrogens regulate, via an ER-mediated pathway, gene expression of cyclins, kinases, bcl-2 proto-oncogene, activation-induced deaminase (AID), and transcription factors, associated with changes in BCR signaling and B cell tumorigenesis. In conclusion, estrogen receptors play an important role in normal B-cell function and B-cell tumorigenesis; however, further investigations are required to delineate the role of estrogens and estrogen receptors in the etiopathogenesis and therapy of B-cell malignancies. © 2016 Informa UK Limited, trading as Taylor &amp; Francis Group