Multiplex immunohistochemistry elucidates increased distance between cytotoxic T cells and plasma cells in relapsed myeloma, and identifies Lag-3 as the most common checkpoint receptor on cytotoxic T cells of myeloma patients.

A dysfunctional immune tumor microenvironment facilitates disease progression in multiple myeloma (MM). Using multiplex immunohistochemistry (mIHC), we describe the quantitative and qualitative changes in CD3+CD8+ cytotoxic T cells and assess their proximity to malignant plasma cells (PC) in patients with monoclonal gammopathy of undetermined significance (MGUS), and newly diagnosed (ND) and relapsed and/or refractory (RR) MM. Formalin-fixed, paraffin-embedded trephine sections from patients with MGUS (N=32), NDMM (N=65), and RRMM (N=59) were sequentially stained for CD138, CD3, CD8, and checkpoint receptors (CPR) Tim-3, Lag-3, and PD-1.

Adult murine hematopoietic stem cells and progenitors: an update on their identities, functions, and assays.

The founder of all blood cells are hematopoietic stem cells (HSCs), which are rare stem cells that undergo key cell fate decisions to self-renew to generate more HSCs or to differentiate progressively into a hierarchy of different immature hematopoietic cell types to ultimately produce mature blood cells. These decisions are influenced both intrinsically and extrinsically, the latter by microenvironment cells in the bone marrow (BM). In recent decades, notable progress in our ability to identify, isolate, and study key properties of adult murine HSCs and multipotent progenitor (MPP) cells has challenged our prior understanding of the hierarchy of these primitive hematopoietic cells.

Gender inequities in medical research funding is driving an exodus of women from Australian STEMM academia.

Universally, women are under-represented in senior academic leadership in science, technology, engineering, maths and medicine (STEMM). Successful funding outcomes are a critical point in career progression, to continue both a scientist's research but also for their retention within the STEMM workforce. A common explanation for the lower success rate of women in securing funding is that fewer women apply for funding.

Loss of Parathyroid Hormone Receptor Signaling in Osteoprogenitors Is Associated With Accumulation of Multiple Hematopoietic Lineages in the Bone Marrow.

Osteoblasts and their progenitors play an important role in the support of hematopoiesis within the bone marrow (BM) microenvironment. We have previously reported that parathyroid hormone receptor (PTH1R) signaling in osteoprogenitors is required for normal B cell precursor differentiation, and for trafficking of maturing B cells out of the BM. Cells of the osteoblast lineage have been implicated in the regulation of several other hematopoietic cell populations, but the effects of PTH1R signaling in osteoprogenitors on other maturing hematopoietic populations have not been investigated.

From the niche to malignant hematopoiesis and back: reciprocal interactions between leukemia and the bone marrow microenvironment.

The bone marrow microenvironment (BMME) regulates hematopoiesis through a complex network of cellular and molecular components. Hematologic malignancies reside within, and extensively interact with, the same BMME. These interactions consequently alter both malignant and benign hematopoiesis in multiple ways, and can encompass initiation of malignancy, support of malignant progression, resistance to chemotherapy, and loss of normal hematopoiesis.

Human, mouse, and dog bone marrow show similar mesenchymal stromal cells within a distinctive microenvironment.

Bone marrow stromal cells (BMSCs) are a key part of the hematopoietic niche. Mouse and human BMSCs are recognized by different markers (LepR and NGFR/CD271, respectively). However, there has not been a detailed in situ comparison of both populations within the hematopoietic microenvironment.

Regulation of murine B lymphopoiesis by stromal cells.

B lymphocytes are crucial for the body's humoral immune response, secreting antibodies generated against foreign antigens to fight infection. Adult murine B lymphopoiesis is initiated in the bone marrow and additional maturation occurs in the spleen. In both these organs, B lymphopoiesis involves interactions with numerous different non-hematopoietic cells, also known as stromal or microenvironment cells, which provide migratory, maturation, and survival signals.

The characterization of distinct populations of murine skeletal cells that have different roles in B lymphopoiesis.

Hematopoiesis is extrinsically controlled by cells of the bone marrow microenvironment, including skeletal lineage cells. The identification and subsequent studies of distinct subpopulations of maturing skeletal cells is currently limited because of a lack of methods to isolate these cells. We found that murine Lin-CD31-Sca-1-CD51+ cells can be divided into 4 subpopulations by using flow cytometry based on their expression of the platelet-derived growth factor receptors ⍺ and β (PDGFR⍺ and PDGFRβ).

Sugar Rush: Supercharging Blood Cell Specification via the Inflammasome.

The generation of adult hematopoietic stem and progenitor cells (HSPCs) from embryonic and induced pluripotent stem cells (iPSCs) will provide therapeutic benefits but is currently elusive. In this issue of Developmental Cell, Frame et al. reveal that the inflammasome has a key role in HSPCs specification during endothelial-to-hematopoietic transition (EHT).

retinoic acid in non-promyelocytic acute myeloid leukemia: driver lesion dependent effects on leukemic stem cells.

Acute myeloid leukemia (AML) is an aggressive, often fatal hematopoietic malignancy. retinoic acid (atRA), one of the first molecularly targeted drugs in oncology, has greatly improved the outcome of a subtype of AML, acute promyelocytic leukemia (APL). In contrast, atRA has so far provided little therapeutic benefit in the much larger group of patients with non-APL AML.

Effects of chemotherapy agents used to treat pediatric acute lymphoblastic leukemia patients on bone parameters and longitudinal growth of juvenile mice.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Therapies for pediatric ALL have improved such that more than 80% of patients survive to 5 years post-therapy, and most survive to adulthood. These ALL patients experience long-term side effects that permanently affect their quality of life, with bone loss and reduced longitudinal growth being the most common skeletal complications.

All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia.

Ecotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs.

A population of nonneuronal GFRα3-expressing cells in the bone marrow resembles nonmyelinating Schwann cells.

Artemin is a neurotrophic factor that plays a crucial role in the regulation of neural development and regeneration and has also been implicated in the pathogenesis of inflammatory pain. The receptor for artemin, GFRα3, is expressed by sympathetic and nociceptive sensory neurons, including some that innervate the bone marrow, but it is unclear if it is also expressed in other cell types in the bone marrow. Our goal in the present study was to characterise the expression of GFRα3 in nonneuronal cells in the bone marrow.

Hemopoietic Cell Kinase amplification with Protein Tyrosine Phosphatase Receptor T depletion leads to polycythemia, aberrant marrow erythoid maturation, and splenomegaly.

Deletion of long arm of chromosome 20 [del(20q)] is the second most frequent recurrent chromosomal abnormality in hematological malignancies. It is detected in 10% of myeloproliferative neoplasms, 4-5% of myelodysplastic syndromes, and 1-2% of acute myeloid leukaemia. Recurrent, non-random occurrence of del(20q) indicates that it is a pathogenic driver in myeloid malignancies.

The haematopoietic stem cell niche: a new player in cardiovascular disease?

Haematopoiesis, the process of blood production, can be altered during the initiation or progression of many diseases. Cardiovascular disease (CVD) has been shown to be heavily influenced by changes to the haematopoietic system, including the types and abundance of immune cells produced. It is now well established that innate immune cells are increased in people with CVD, and the mechanisms contributing to this can be vastly different depending on the risk factors or comorbidities present.

Modeling human RNA spliceosome mutations in the mouse: not all mice were created equal.

Myelodysplastic syndromes (MDS) and related myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are clonal stem cell disorders, primarily affecting patients over 65 years of age. Mapping of the MDS and MDS/MPN genome identified recurrent heterozygous mutations in the RNA splicing machinery, with the SF3B1, SRSF2, and U2AF1 genes being frequently mutated. To better understand how spliceosomal mutations contribute to MDS pathogenesis in vivo, numerous groups have sought to establish conditional murine models of SF3B1, SRSF2, and U2AF1 mutations.

mTORC1 plays an important role in osteoblastic regulation of B-lymphopoiesis.

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 development results in defective bone development in mice. In this study, we now demonstrate that mTORC1 signalling in pre-osteoblasts is required for normal B-lymphocyte development in mice.

Protagonist or antagonist? The complex roles of retinoids in the regulation of hematopoietic stem cells and their specification from pluripotent stem cells.

Hematopoietic stem cells (HSCs) are multipotent cells responsible for the maintenance of the hematopoietic system throughout life. Dysregulation of the balance in HSC self-renewal, death, and differentiation can have serious consequences such as myelodysplastic syndromes or leukemia. All-trans retinoic acid (ATRA), the biologically active metabolite of vitamin A/RA, has been shown to have pleiotropic effects on hematopoietic cells, enhancing HSC self-renewal while also increasing differentiation of more mature progenitors.

initiates myeloid bias and myelodysplastic/myeloproliferative syndrome from hemopoietic stem cells.

Mutations in occur in myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPN). mutations cluster at proline 95, with the most frequent mutation being a histidine (P95H) substitution. They undergo positive selection, arise early in the course of disease, and have been identified in age-related clonal hemopoiesis.

Imaging methods used to study mouse and human HSC niches: Current and emerging technologies.

Bone marrow contains numerous different cell types arising from hematopoietic stem cells (HSCs) and non-hematopoietic mesenchymal/skeletal stem cells, in addition to other cell types such as endothelial cells- these non-hematopoietic cells are commonly referred to as stromal cells or microenvironment cells. HSC function is intimately linked to complex signals integrated by their niches, formed by combinations of hematopoietic and stromal cells. Studies of hematopoietic cells have been significantly advanced by flow cytometry methods, enabling the quantitation of each cell type in normal and perturbed situations, in addition to the isolation of these cells for molecular and functional studies.

Inhibition of Endosteal Vascular Niche Remodeling Rescues Hematopoietic Stem Cell Loss in AML.

Bone marrow vascular niches sustain hematopoietic stem cells (HSCs) and are drastically remodeled in leukemia to support pathological functions. Acute myeloid leukemia (AML) cells produce angiogenic factors, which likely contribute to this remodeling, but anti-angiogenic therapies do not improve AML patient outcomes. Using intravital microscopy, we found that AML progression leads to differential remodeling of vasculature in central and endosteal bone marrow regions.