A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies

Tomasoni, Chiara; Pievani, Alice; Rambaldi, Benedetta; Biondi, Andrea; Serafini, Marta

doi:10.1097/hs9.0000000000000896

Cited by 3 publications

(2 citation statements)

References 100 publications

(250 reference statements)

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“…However they can be regarded as useful tools to target leukemic stem cells aggregates which frequently form in bone marrow niches and can cause relapse of the disease. The formation of stem cells aggregates is favoured by survival of tumor cells to therapy caused by scarce penetration of free drugs in bone marrow 56 , 57 . Accumulation of drug-loaded nanoparticles in bone marrow is a well-known event associated with nanoparticles injection for treatment of solid tumors.…”

Section: Discussionmentioning

confidence: 99%

Nano-fenretinide demonstrates remarkable activity in acute promyeloid leukemia cells

Farruggia,

Anconelli,

Galassi

et al. 2024

Sci Rep

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Acute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective in the treatment of this disease, inducing promyelocytes differentiation. Current therapy, based on ATRA in combination with arsenic trioxide, with or without chemotherapy, provides high rates of event-free survival and overall survival. However, a decline in the drug activity, due to increased ATRA metabolism and RARα mutations, is often observed over long-term treatments. Furthermore, dedifferentiation can occur providing relapse of the disease. In this study we evaluated fenretinide, a semisynthetic ATRA derivative, encapsulated in nanomicelles (nano-fenretinide) as an alternative treatment to ATRA in APL. Nano-fenretinide was prepared by fenretinide encapsulation in a self-assembling phospholipid mixture. Physico-chemical characterization was carried out by dinamic light scattering and spectrophotometry. The biological activity was evaluated by MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy. Nano-fenretinide induced apoptosis in acute promyelocytic leukemia cells (HL60) by an early increase of reactive oxygen species and a mitochondrial potential decrease. The fenretinide concentration that induced 90–100% decrease in cell viability was about 2.0 µM at 24 h, a concentration easily achievable in vivo when nano-fenretinide is administered by oral or intravenous route, as demonstrated in previous studies. Nano-fenretinide was effective, albeit at slightly higher concentrations, also in doxorubicin-resistant HL60 cells, while a comparison with TK6 lymphoblasts indicated a lack of toxicity on normal cells. The results indicate that nano-fenretinide can be considered an alternative therapy to ATRA in acute promyelocytic leukemia when decreased efficacy, resistance or recurrence of disease emerge after protracted treatments with ATRA.

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Section: Discussionmentioning

confidence: 99%

Nano-fenretinide demonstrates remarkable activity in acute promyeloid leukemia cells

Farruggia,

Anconelli,

Galassi

et al. 2024

Sci Rep

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show abstract

“…Prevailing studies intimate that the immunological equilibrium within the bone marrow microenvironment is pivotal in AML’s immunotherapy and other treatments such as chemotherapy and targeted therapy [ 10 ]. Tumor cells manipulate and remodel the BM ecology, converting it into a configuration that shields the tumor, facilitating AML’s immune evasion, and bolstering resistance to treatments [ 11 ]. Within this aberrant BM setting, AML stem and progenitor cells retain their regenerative capacities, while residual lesions receive conducive sustenance, precipitating AML relapse [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal evolution of AML immune microenvironment remodeling and RNF149-driven drug resistance through single-cell multidimensional analysis

Wu,

Deng

et al. 2023

J Transl Med

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Background The composition of the bone marrow immune microenvironment in patients with acute myeloid leukaemia (AML) was analysed by single-cell sequencing and the evolutionary role of different subpopulations of T cells in the development of AML and in driving drug resistance was explored in conjunction with E3 ubiquitin ligase-related genes. Methods To elucidate the mechanisms underlying AML-NR and Ara-C resistance, we analyzed the bone marrow immune microenvironment of AML patients by integrating multiple single-cell RNA sequencing datasets. When compared to the AML disease remission (AML-CR) cohort, AML-NR displayed distinct cellular interactions and alterations in the ratios of CD4+T, Treg, and CD8+T cell populations. Results Our findings indicate that the E3 ubiquitin ligase RNF149 accelerates AML progression, modifies the AML immune milieu, triggers CD8+T cell dysfunction, and influences the transformation of CD8+ Navie.T cells to CD8+TExh, culminating in diminished AML responsiveness to chemotherapeutic agents. Experiments both in vivo and in vitro revealed RNF149’s role in enhancing AML drug-resistant cell line proliferation and in apoptotic inhibition, fostering resistance to Ara-C. Conclusion In essence, the immune microenvironments of AML-CR and AML-NR diverge considerably, spotlighting RNF149’s tumorigenic function in AML and cementing its status as a potential prognostic indicator and innovative therapeutic avenue for countering AML resistance. Graphical Abstract

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Spatial-transcriptomic profiling: a new lens for understanding myelofibrosis pathophysiology

Peroni,

Calistri,

Amato

et al. 2024

Cell Commun Signal

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Myelofibrosis (MF) is a complex myeloproliferative neoplasm characterized by abnormal hematopoietic stem cell proliferation and subsequent bone marrow (BM) fibrosis. First documented in the late 19th century, MF has since been extensively studied to unravel its pathophysiology, clinical phenotypes, and therapeutic interventions. MF can be classified into primary and secondary forms, both driven by mutations in genes such as JAK2, CALR, and MPL, which activate the JAK-STAT signaling pathway. These driver mutations are frequently accompanied by additional non-driver mutations in genes like TET2, SRSF2, and TP53, contributing to disease complexity. The BM microenvironment, consisting of stromal cells, extracellular matrix, and cytokines such as TGF-β and TNF-α, plays a critical role in fibrosis and aberrant hematopoiesis. Clinically, MF manifests with symptoms ranging from anemia, splenomegaly, and fatigue to severe complications such as leukemic transformation. Splenomegaly, caused by extramedullary hematopoiesis, leads to abdominal discomfort and early satiety. Current therapeutic strategies include JAK inhibitors like Ruxolitinib, which target the JAK-STAT pathway, alongside supportive treatments such as blood transfusions, erythropoiesis-stimulating agents and developing combinatorial approaches. Allogeneic hematopoietic stem cell transplantation remains the only curative option, though it is limited to younger, high-risk patients. Recently approved JAK inhibitors, including Fedratinib, Pacritinib, and Momelotinib, have expanded the therapeutic landscape. Spatially Resolved Transcriptomics (SRT) has revolutionized the study of gene expression within the spatial context of tissues, providing unprecedented insights into cellular heterogeneity, spatial gene regulation, and microenvironmental interactions, including stromal-hematopoietic dynamics. SRT enables high-resolution mapping of gene expression in the BM and spleen, revealing molecular signatures, spatial heterogeneity, and pathological niches that drive disease progression. These technologies elucidate the role of the spleen in MF, highlighting its transformation into a site of abnormal hematopoietic activity, fibrotic changes, and immune cell infiltration, functioning as a “tumor surrogate.” By profiling diverse cell populations and molecular alterations within the BM and spleen, SRT facilitates a deeper understanding of MF pathophysiology, helping identify novel therapeutic targets and biomarkers. Ultimately, integrating spatial transcriptomics into MF research promises to enhance diagnostic precision and therapeutic innovation, addressing the multifaceted challenges of this disease.

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A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies

Cited by 3 publications

References 100 publications

Nano-fenretinide demonstrates remarkable activity in acute promyeloid leukemia cells

Nano-fenretinide demonstrates remarkable activity in acute promyeloid leukemia cells

Spatiotemporal evolution of AML immune microenvironment remodeling and RNF149-driven drug resistance through single-cell multidimensional analysis

Spatial-transcriptomic profiling: a new lens for understanding myelofibrosis pathophysiology

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