Andrew C. W. Zannettino

• The University of Adelaide

The risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) increases with advancing age, suggesting that progression may be influenced by age-related changes within the bone marrow (BM) microenvironment. We hypothesise that senescent mesenchymal stromal cells (MSCs), which accumulate in the BM with...

Paediatric patients with relapsed B cell acute lymphoblastic leukaemia (B-ALL) have poor prognosis, as relapse-causing clones are often refractory to common chemotherapeutics. While the molecular mechanisms leading to chemoresistance are varied, significant evidence suggests interactions between B-ALL blasts and cells within the bone marrow microen...

Multiple myeloma (MM) is an incurable haematological malignancy characterised by the uncontrolled proliferation of bone marrow resident plasma cells (PCs). Two members of the TAM (TYRO3, AXL and MER) receptor family have previously been implicated in distinct aspects of neoplastic PC biology. AXL expression in MM PCs has been associated with induct...

The cell adhesion molecule N-cadherin (CDH2) is a membrane component of adherens junctions which regulates tissue morphogenesis and architecture. In the follicles of mammalian ovaries, N-cadherin adherens junctions are present between granulosa cells, cumulus cells and at the interface of cumulus cell transzonal projections and the oocyte. We demon...

The cell adhesion molecule N-cadherin (CDH2) is a membrane component of adherens junctions which regulates tissue morphogenesis and architecture. In the follicles of mammalian ovaries, N-cadherin adherens junctions are present between granulosa cells, cumulus cells and at the interface of cumulus cell transzonal projections and the oocyte. We demon...

Multiple myeloma (MM) is an incurable malignancy characterised by uncontrolled proliferation of plasma cells (PCs) in the bone marrow (BM). MM is a genetically heterogeneous disease with each patient's PCs harbouring unique genetic mutations, however the development of MM tumours is not only dependent on the underlying genetics but also on the sele...

Despite major improvements in therapeutic strategies for patients with multiple myeloma (MM), effective treatment still remains a persistent challenge, as patients ultimately relapse and succumb to the disease. In the last decade, studies have highlighted the reciprocal interaction between MM plasma cells (PC) and the bone marrow (BM) microenvironm...

Expression of myeloperoxidase (MPO), a key inflammatory enzyme restricted to myeloid cells, is negatively associated with the development of solid tumours. Activated myeloid cell populations are increased in multiple myeloma (MM); however, the functional consequences of myeloid‐derived MPO within the myeloma microenvironment are unknown. Here, the...

Multiple myeloma (MM) is a disease of older people, yet factors relating to comorbidity and frailty may threaten treatment tolerability for many of this heterogeneous group. There has been increasing interest in defining specific and clinically relevant frailty assessment tools within the MM population, with the goal of using these frailty scores n...

Acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), and multiple myeloma (MM) are age-related haematological malignancies with defined precursor states termed myelodysplastic syndrome (MDS), monoclonal B-cell lymphocytosis (MBL), and monoclonal gammopathy of undetermined significance (MGUS), respectively. While the progression from...

Waldenström Macroglobulinaemia (WM) is an indolent B‐cell malignancy characterised by the presence of IgM paraprotein, bone marrow infiltration by clonal small B lymphocytes with plasmacytic differentiation, and the MYD88 L265P mutation in >90% of cases. Traditionally, WM has been treated with chemoimmunotherapy. Recent trials have demonstrated the...

Elucidation of the molecular signatures that define hematopoietic tissue resident macrophage specialisation has been challenging. There are no validated markers that differentiate the specialised macrophage subsets in bone marrow (BM) that support erythropoiesis, bone homeostasis and hematopoietic stem cell (HSC) niches. We took an unbiased ex vivo...

Multiple myeloma (MM) is an incurable haematological malignancy, caused by the uncontrolled proliferation of plasma cells within the bone marrow (BM). Obesity is a known risk factor for MM, however, few studies have investigated the potential of dietary intervention to prevent MM progression. Calorie restriction (CR) is associated with many health...

Stem cell therapy using mesenchymal stem/stromal cells (MSCs) represents a novel approach to treating severe diseases, including osteoarthritis. However, the therapeutic benefit of MSCs is highly dependent on their differentiation state, which can be regulated by many factors. Herein, three-dimensional (3D) magnetic scaffolds were successfully fabr...

Overnutrition causes hyperactivation of mTORC1-dependent negative feedback loops leading to the downregulation of insulin signaling and development of insulin resistance. In osteoblasts (OBs), insulin signaling plays a crucial role in the control of systemic glucose homeostasis. We utilized mice with conditional deletion of Rptor to investigate how...

Mouse hematopoietic tissues contain abundant tissue-resident macrophages that support immunity, hematopoiesis, and bone homeostasis. A systematic strategy to characterize macrophage subsets in mouse bone marrow (BM), spleen, and lymph node unexpectedly reveals that macrophage surface marker staining emanates from membrane-bound subcellular remnants...

Multiple myeloma (MM) is the second most common hematological malignancy and is an incurable disease of neoplastic plasma cells (PC). Newly‐diagnosed MM patients currently undergo lengthy genetic testing to match chromosomal mutations with the most potent drug/s to decelerate disease progression. With only 17% of MM patients surviving 10‐years post...

Bone defects arising from fractures or disease represent a significant problem for surgeons to manage and are a substantial economic burden on the healthcare economy. Recent advances in the development of biomaterial substitutes provides an attractive alternative to the current “gold standard” autologous bone grafting. Despite on-going research, we...

The mammalian target of rapamycin complex 1 (mTORC1) complex is the major nutrient sensor in mammalian cells that responds to amino acids, energy levels, growth factors, and hormones, such as insulin, to control anabolic and catabolic processes. We have recently shown that suppression of the mTORC1 complex in bone-forming osteoblasts (OBs) improved...

Macrophages are a vital component of the tumour microenvironment and crucial mediators of tumour progression. In the last decade, significant strides have been made in understanding the crucial functional roles played by macrophages in the development of the plasma cell (PC) malignancy, multiple myeloma (MM). Whilst the interaction between MM PC an...

Disease relapse is the greatest cause of treatment failure in paediatric B‐cell acute lymphoblastic leukaemia (B‐ALL). Current risk stratifications fail to capture all patients at risk of relapse. Herein, we used a machine‐learning approach to identify B‐ALL blast‐secreted factors that are associated with poor survival outcomes. Using this approach...

eIF4E plays key roles in protein synthesis and tumorigenesis. It is phosphorylated by the kinases MNK1 and MNK2. Binding of MNKs to eIF4G enhances their ability to phosphorylate eIF4E. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs bind...

Simple Summary Like in solid cancers, the process of dissemination is a critical feature of disease progression in the blood cancer multiple myeloma. At diagnosis, myeloma patients have cancer that has spread throughout the bone marrow, with patients with more disseminatory myeloma having worse outcomes for their disease. In this review, we discuss...

Multiple myeloma (MM) disease progression is dependent on the ability of MM plasma cells (PCs) to egress from the bone marrow (BM), enter the circulation and disseminate to distal BM sites. Expression of the chemokine CXCL12 by BM stromal cells is crucial for MM PC retention within the BM. However, the mechanisms which overcome CXCL12-mediated rete...

Background and aims Cancer-associated fibroblasts (CAF), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogene...

The protein SAMSN1 was recently identified as a putative tumour suppressor in multiple myeloma, with re‐expression of Samsn1 in the 5TGM1/KaLwRij murine model of myeloma leading to a near complete abrogation of intramedullary tumour growth. Here, we sought to clarify the mechanism underlying this finding. Intratibial administration of 5TGM1 myeloma...

In most instances, multiple myeloma (MM) plasma cells (PCs) are reliant on factors made by cells of the bone marrow (BM) stroma for their survival and growth. To date, the nature and cellular composition of the BM tumor microenvironment and the critical factors which drive tumor progression remain imprecisely defined. Our studies show that Gremlin1...

The cover image is derived from the images of the original research article "Fabrication of a Cartilage Patch by Fusing Hydrogel-Derived Cell Aggregates onto Electrospun Film" published in Tissue Engineering Part A. (https://www.liebertpub.com/doi/10.1089/ten.TEA.2019.0318)

Cell aggregates are widely used either as in-vitro models for drug screening, fundamental studies on disease progression and developmental biology, as well as in-vivo injectable cells for tissue regeneration. Compared to single-cell suspensions, cell aggregates retain superior cell viability, mimic in-vivo microenvironments and enhance functional p...

N‐cadherin is a homophilic cell‐cell adhesion molecule that plays a critical role in maintaining vascular stability and modulating endothelial barrier permeability. Pre‐clinical studies have shown that the N‐cadherin antagonist peptide, ADH‐1, increases the permeability of tumour‐associated vasculature thereby increasing anti‐cancer drug delivery t...

Because of important functions of skin, an effective therapy is demanded for serious full-thickness skin injuries. In this study, a thermosensitive poly (N-isopropylacrylamide-co-acrylic acid) (p(NIPAAm-AA) hydrogel was prepared and successfully used for different 3D printing methods, including 3D printing with a single needle nozzle and a single s...

P0-related protein (PZR), a Noonan and LEOPARD syndrome target, is a member of the transmembrane Immunoglobulin superfamily. Its cytoplasmic tail contains two immune-receptor tyrosine-based inhibitory motifs (ITIMs), implicated in adhesion-dependent signaling and regulating cell adhesion and motility. PZR promotes cell migration on the extracellula...

Many of the skeletal tissue regenerative strategies centre around the multifunctional properties of bone marrow derived stromal cells (BMSC) or mesenchymal stem/stromal cells (MSC)/bone marrow derived skeletal stem cells. Specific identification of these particular stem cells has been inconclusive. However, enriching these heterogeneous bone marrow...

Irregular defects at sites of degenerative cartilage often accompany osteoarthritis (OA). The development of novel cells/biomaterials-based cartilage tissue engineering methods to address these defects may provide a durable approach to hinder the development of OA. In the present study, we fabricated a neo-cartilage patch by fusing cell aggregates...

Approximately 15% of patients with multiple myeloma (MM) harbour the t(4;14) chromosomal translocation, leading to the overexpression of the histone methyltransferase NSD2. Patients with this translocation display increased tumour dissemination, accelerated disease progression and rapid relapse. Using publicly available gene expression profile data...

Multiple myeloma, a plasma cell malignancy, is a genetically heterogeneous disease and the genetic factors that contribute to its development and progression remain to be fully elucidated. The tumour suppressor gene GLIPR1 has previously been shown to be deleted in approximately 10% of myeloma patients, to inhibit the development of plasma cell tum...

Biomimetic hydrogels offer a new platform for hierarchical structure controlled tough, biocompatible, mechanically tunable and printable gels for regenerative medicine. Herein we report for the first time, the detailed effects of various kinds of nanocellulose namely, bacterial nanocellulose (BC), cellulose nanofibers (CNF) and cellulose nanocrysta...

The Eph receptor tyrosine kinase ligand, ephrinB1 (EfnB1) is important for correct skeletal and cartilage development, however, the role of EfnB1 in fracture repair is unknown. This study investigated the role of EfnB1 during fracture repair where EfnB1 expression increased significantly at 1 and 2 weeks post fracture in C57Bl/6 wildtype mice, coin...

Osteoarthritis (OA) is an inflammation-related chronic disease that causes progressive degeneration of cartilage, which might even extend to subchondral bones. Due to the unique physiological structural differences between cartilage and subchondral bone, it is challenging to restore the full function of an osteochondral defect. In this study, a the...

The era of targeted therapies has seen significant improvements in depth of response, progression- free survival, and overall survival for patients with multiple myeloma. Despite these improvements in clinical outcome, patients inevitably relapse and require further treatment. Drug-resistant dormant myeloma cells that reside in specific niches with...

Multiple myeloma (MM) is a largely incurable haematological malignancy defined by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow. Clonal heterogeneity has recently been established as a feature in MM, however, the subclonal evolution associated with disease progression has not been described. Here, we performed whol...

Background The 5 hydroxymethylation (5hmC) mark and TET DNA dioxygenases play a pivotal role in embryonic stem cell differentiation and animal development. However, very little is known about TET enzymes in lineage determination of human bone marrow-derived mesenchymal stem/stromal cells (BMSC). We examined the function of all three TET DNA dioxyge...

Recurrent oncogenic fusion genes play a critical role in the development of various cancers and diseases and provide, in some cases, excellent therapeutic targets. To date, analysis tools that can identify and compare recurrent fusion genes across multiple samples have not been available to researchers. To address this deficiency, we developed Co-o...

In many types of solid tumours, the aberrant expression of the cell adhesion molecule N-cadherin is a hallmark of epithelial-to-mesenchymal transition, resulting in the acquisition of an aggressive tumour phenotype. This transition endows tumour cells with the capacity to escape from the confines of the primary tumour and metastasise to secondary s...

The bone marrow stromal microenvironment contributes to the maintenance and function of hematopoietic stem/progenitor cells (HSPCs). The Eph receptor tyrosine kinase family members have been implicated in bone homeostasis and stromal support of HSPCs. The present study examined the influence of EfnB1-expressing osteogenic lineage on HSPC function....

Abstract Skeletal osteoblasts are important regulators of B-lymphopoiesis, serving as a rich source of factors such as CXCL12 and IL-7 which are crucial for B-cell development. Recent studies from our laboratory and others have shown that deletion of Rptor, a unique component of the mTORC1 nutrient-sensing complex, early in the osteoblast lineage d...

Key transcription factors, which activate or repress master gene regulators and signaling pathways, tightly regulate self-renewal and cell lineage differentiation of bone marrow-derived stromal cells (BMSC). Among these factors is the basic helix-loop-helix transcription factor Twist-related protein 1 (TWIST-1), which is important in BMSC self-rene...

The present study investigated the effects of conditional deletion of ephrinB1 in osteoprogenitor cells driven by the Osterix (Osx) promoter, on skeletal integrity in a murine model of ovariectomy-induced (OVX) osteoporosis. Histomorphometric and μCT analyses revealed that loss of ephrinB1 in sham Osx:cre-ephrinB1fl/fl mice caused a reduction in tr...

Human mesenchymal stem/stromal cells (hMSCs) are a potential cell source of stem cell therapy for many serious diseases and hMSC spheroids have emerged to replace single cell suspensions for cell therapy. Three dimensional (3D) scaffolds or hydrogels which can mimic properties of the extracellular matrix (ECM) have been widely explored for their ap...

Bone repair: Magnetic nanoparticle therapy helps fix bone injuries in sheep A biomagnetic therapy that stimulates adult stem cells helps promote repair in a sheep model of bone injury. Alicia El Haj from Keele University, UK, and colleagues previously developed a technique for activating specific ion channel receptors on stem cells through the use...

Background: The pharmaceutical agent pentosan polysulfate (PPS) is known to induce proliferation and chondrogenesis of mesenchymal progenitor cells (MPCs) in vitro and in vivo. However, the mechanism(s) of action of PPS in mediating these effects remains unresolved. In the present report we address this issue by investigating the binding and uptak...

Filtering rare barcodes for sample uniqueness. The uniqueness of all the barcodes of the rare (<0.1%) subclass is shown. A comparison to the numbers of common (>5%) subclass of barcodes per sample (from Figure 3) is shown.

In vitro and in vivo barcode data from pilot experiments. The sequences and read counts of all the barcodes detected in day 0 and day 28 in vitro 5TGM1 cultures, and tumors from the individual long bones of 5 mice on day 28 are shown. Frequencies of the rare (<0.1%) and common (>5%) subclasses of barcodes are also shown. Key: L/R = left/right. F/T...

Deep sequencing of single barcode control cell lines. Read counts, mismatch data, and frequency distributions are shown for NGS of PCR products from 5TGM1 clones #23 and #31, each of which contains a single DNA barcode (shaded yellow and green, respectively). Read counts are also shown for deep sequencing of PCR products derived from admixtures of...

Common subclasses of barcodes in pilot in vivo experiment. The sequences and read counts for all 78 barcodes that were classified as common (each representing at least 5% of the bulk of their respective tumors) in individual long bones from n = 5 different mice. Key: L/R = left/right. F/T = femur/tibia.

Uniqueness of the common subclass of barcodes. The read counts for each common (>5%) barcode are shown together with their bone of origin and whether they were detectable within the common subclass in only one bone and/or one mouse. Barcodes whose frequency subclass was common in more than one long bone in the same mouse are indicated by the same c...

Tumor barcode data from second in vivo experiment. The sequences and read counts are shown for all barcodes detected in both replicate PCR products generated from tumors in the indicated long bones. Only those barcodes seen in the reference library of barcodes are shown. Sequences with less than 3 mismatches from barcodes with >10,000 read counts h...

Multiple myeloma (MM) is a hematological malignancy resulting from the uncontrolled proliferation of antibody-producing plasma cells in the bone marrow. At diagnosis, independent plasma cell tumors are found throughout the skeleton. The recirculation of mutant plasma cells from the initial lesion and their recolonization of distant marrow sites are...

Background context: Neural compression associated with lumbar disc herniation is usually managed surgically by microdiscectomy. However, 10 - 20% patients re-present with debilitating back pain and approximately 15% require further surgery. Purpose: Using an ovine model of microdiscectomy, the present study investigated the relative potential of...

Saethre–Chotzen syndrome (SCS), associated with TWIST‐1 mutations, is characterized by premature fusion of cranial sutures. TWIST‐1 haploinsufficiency, leads to alterations in suture mesenchyme cellular gene expression patterns, resulting in aberrant osteogenesis and craniosynostosis. We analyzed the expression of the TWIST‐1 target, Tyrosine kinas...

Disease progression and relapse in multiple myeloma (MM) is dependent on the ability of the MM plasma cells (PC) to re-enter the circulation and disseminate throughout the bone marrow. Increased bone marrow hypoxia is associated with increased recirculation of MM PC. Accordingly, we hypothesised that during chronic hypoxia activation of HIF-2α may...

Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia also leads to treatment opportunities as demonstrated by the development of compounds that target regions of hypoxia within tumors. Evofosfamide is a hypoxia-activated prodrug that is created by linking the hypoxia-seeking 2-nitroimidazole moiety to...

Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of plasma cells in the bone marrow. More than 80% of patients with MM display evidence of myeloma bone disease (MBD), characterised by the formation of osteolytic lesions throughout the axial and appendicular skeleton. MBD significantly increases the risk...

Multiple Myeloma (MM) is a haematological malignancy characterised by the clonal expansion of plasma cells (PCs) within the bone marrow. Despite advances in therapy, MM remains a largely incurable disease with a median survival of 6 years. In almost all cases, the development of MM is preceded by the benign PC condition Monoclonal Gammopathy of Und...

The proteasome inhibitor bortezomib has proven to be invaluable in the treatment of myeloma. By exploiting the inherent high immunoglobulin protein production of malignant plasma cells, bortezomib induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), resulting in myeloma cell death. In most cases, however, the disease r...