scholarly journals Preclinical models of human multiple myeloma subgroups

2021 ◽  
Author(s):  
Wiebke Winkler ◽  
Carlota Farré Díaz ◽  
Eric Blanc ◽  
Hanna Napieczynska ◽  
Patrick Langner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Germinal Center ◽  
Plasma Cells ◽  
Bone Lesions ◽  
Preclinical Models ◽  
Co Activation ◽  
Human Multiple Myeloma ◽  
First Time

Multiple myeloma (MM), a tumor of germinal center (GC)-experienced plasma cells, comprises distinct genetic subgroups, such as the t(11;14)/CCND1 and the t(4;14)/MMSET subtype. We have generated subgroup-specific MM models by the GC B cell-specific co-activation of Ccnd1 or MMSET with a constitutively active Ikk2 mutant, mimicking the secondary NFκB activation frequently seen in human MM. Ccnd1/Ikk2ca and MMSET/Ikk2ca mice developed a pronounced, clonally restricted plasma cell outgrowth with age, accompanied by serum M spikes, bone marrow insufficiency and bone lesions. The transgenic plasma cells could be propagated in vivo and showed transcriptional profiles resembling their human counterparts. Thus, we show that Ccnd1 and MMSET cooperate with NFκB in MM pathogenesis, considering for the first time the genetic heterogeneity of MM for the generation of preclinical models.

scholarly journals 'Role of bone marrow stromal cells in the growth of human multiple myeloma

Blood ◽  
1991 ◽  
Vol 77 (12) ◽  
pp. 2688-2693 ◽  
Author(s):  
F Caligaris-Cappio ◽  
L Bergui ◽  
MG Gregoretti ◽  
G Gaidano ◽  
M Gaboli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Lymphocytes ◽  
Stromal Cells ◽  
Mononuclear Cells ◽  
Plasma Cells ◽  
Critical Role ◽  
Peripheral Blood Mononuclear ◽  
Human Multiple Myeloma

We have verified the hypothesis that multiple myeloma (MM) may be disseminated by circulating clonogenic cells that selectively home to the bone marrow (BM) to receive the signal(s) leading to proliferation, terminal differentiation, and production of the osteoclast activating factors. Long-term cultures of stromal cells have been developed from the BM of nine patients with MM. These cells were mostly fibroblast- like elements, interspersed with a proportion of scattered macrophages and rare osteoclasts. BM stromal cells were CD54+, produced high levels of interleukin-6 (IL-6) and measurable amounts of IL-1 beta, and were used as feeder layers for autologous peripheral blood mononuclear cells (PBMC). After 3 weeks of cocultures, monoclonal B lymphocytes and plasma cells, derived from PBMC, developed and the number of osteoclasts significantly increased. Both populations grew tightly adherent to the stromal cell layer and their expansion was matched by a sharp increase of IL-6 and by the appearance of IL-3 in the culture supernatant. These data attribute to BM stromal cells a critical role in supporting the growth of B lymphocytes, plasma cells, and osteoclasts and the in vivo dissemination of MM.

scholarly journals Mieloma multipel: aspek patogenesis molekuler

2019 ◽  
Vol 3 (1) ◽  
pp. 1-7
Author(s):  
Made Bakta
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Germinal Center ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Somatic Hypermutation ◽  
P53 Mutation ◽  
Bone Lesions ◽  
Genetic Changes ◽  
Clonal Proliferation

Multiple myeloma (MM) is a neoplastic plasma disorder that is characterized by clonal proliferation of malignant plasma cells in the bone marrow, monoclonal protein in the blood or urine and associated organ dysfunction. It is preceded by a premalignant tumor which is share genetic abnormalities, monoclonal gammopathy of undetermined significance (MGUS). Although remarkable progress has been achieved, but pathogenesis of MM is still very complex. Multiple myeloma appears to arise from the malignant transformation of germinal-center B-lymphocyte. The first oncogenic events in MM appear to occur in the germinal center due to error in isotype class switching and somatic hypermutation. MM is divided into two distinct genetic subtypes: (1) hyperdiploid myeloma is characterized by multiple trisomies of chromosome 3, 5, 7, 9, 11, 15, 19 and 21; (2) non-hyperdiploid in contrast is characterized by recurrence translocations t(4;14), t(14;16), t (14;20); t(6;14) and t(11;14). A unifying event in the pathogenesis of MM is the dysregulated expression of cyclin D gene. Genetic aberrations occur in MM and also in premalignant state (MGUS), suggesting that genetic mutations alone are necessary, but not sufficient for myeloma transformation. A “ random second hit model” was proposed. Hypothetical second hits are: additional genetic changes ( RAS mutation, p16 methylation, p53 mutation), proliferation due to cell cycle dysregulation, evasion of programmed cell death and changes in bone marrow microenvironment. A complex interaction with the BM microenvironment , characterized by activation of osteoclast and supression of osteoblast , leads to lytic bone lesions. 

scholarly journals 'Role of bone marrow stromal cells in the growth of human multiple myeloma

Blood ◽  
1991 ◽  
Vol 77 (12) ◽  
pp. 2688-2693 ◽  
Author(s):  
F Caligaris-Cappio ◽  
L Bergui ◽  
MG Gregoretti ◽  
G Gaidano ◽  
M Gaboli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Lymphocytes ◽  
Stromal Cells ◽  
Mononuclear Cells ◽  
Plasma Cells ◽  
Critical Role ◽  
Peripheral Blood Mononuclear ◽  
Human Multiple Myeloma

Abstract We have verified the hypothesis that multiple myeloma (MM) may be disseminated by circulating clonogenic cells that selectively home to the bone marrow (BM) to receive the signal(s) leading to proliferation, terminal differentiation, and production of the osteoclast activating factors. Long-term cultures of stromal cells have been developed from the BM of nine patients with MM. These cells were mostly fibroblast- like elements, interspersed with a proportion of scattered macrophages and rare osteoclasts. BM stromal cells were CD54+, produced high levels of interleukin-6 (IL-6) and measurable amounts of IL-1 beta, and were used as feeder layers for autologous peripheral blood mononuclear cells (PBMC). After 3 weeks of cocultures, monoclonal B lymphocytes and plasma cells, derived from PBMC, developed and the number of osteoclasts significantly increased. Both populations grew tightly adherent to the stromal cell layer and their expansion was matched by a sharp increase of IL-6 and by the appearance of IL-3 in the culture supernatant. These data attribute to BM stromal cells a critical role in supporting the growth of B lymphocytes, plasma cells, and osteoclasts and the in vivo dissemination of MM.

Bone disease as the first manifestation of systemic AL-amyloidosis

2020 ◽  
Vol 92 (7) ◽  
pp. 85-89
Author(s):  
L. P. Mendeleeva ◽  
I. G. Rekhtina ◽  
A. M. Kovrigina ◽  
I. E. Kostina ◽  
V. A. Khyshova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Disease ◽  
Plasma Cells ◽  
Interventricular Septum ◽  
Bone Destruction ◽  
Amyloid Deposition ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

scholarly journals An Unprecedented Case of p190 BCR-ABL Chronic Myeloid Leukemia Diagnosed during Treatment for Multiple Myeloma: A Case Report and Review of the Literature

2018 ◽  
Vol 2018 ◽  
pp. 1-5
Author(s):  
Kosuke Miki ◽  
Naoshi Obara ◽  
Kenichi Makishima ◽  
Tatsuhiro Sakamoto ◽  
Manabu Kusakabe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Plasma Cells ◽  
Bone Marrow Examination ◽  
Bone Lesions ◽  
Dexamethasone Treatment ◽  
Lytic Bone Lesions

We report the case of a 76-year-old man who was diagnosed as having chronic myeloid leukemia (CML) with p190 BCR-ABL while receiving treatment for symptomatic multiple myeloma (MM). The diagnosis of MM was based on the presence of serum M-protein, abnormal plasma cells in the bone marrow, and lytic bone lesions. The patient achieved a partial response to lenalidomide and dexamethasone treatment. However, 2 years after the diagnosis of MM, the patient developed leukocytosis with granulocytosis, anemia, and thrombocytopenia. Bone marrow examination revealed Philadelphia chromosomes and chimeric p190 BCR-ABL mRNA. Fluorescence in situ hybridization also revealed BCR-ABL-positive neutrophils in the peripheral blood, which suggested the emergence of CML with p190 BCR-ABL. The codevelopment of MM and CML is very rare, and this is the first report describing p190 BCR-ABL-type CML coexisting with MM. Moreover, we have reviewed the literature regarding the coexistence of these diseases.

scholarly journals The Evolution in The Treatment of Multiple Myeloma Towards Targeted Magnetic Molecularly Imprinted Nanomedicines

2015 ◽  
pp. 1-2
Author(s):  
Edgar Pérez-Herrero
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bacterial Infections ◽  
Plasma Cells ◽  
The Body ◽  
Western World ◽  
Bone Lesions ◽  
Non Hodgkin Lymphoma ◽  
Clonal Proliferation ◽  
Tract Infections

Multiple myeloma is the second more frequently haematological cancer in the western world, after non-Hodgkin lymphoma, being about the 1-2 % of all the cancers cases and the 10-13% of hematologic diseases. The disease is caused by an uncontrolled clonal proliferation of plasma cells in the bone marrow that accumulate in different parts of the body, usually in the bone marrow, around some bones, and rarely in other tissues, forming tumor deposits, called plasmocytomas. This uncontrolled clonal proliferation of plasma cells produces the secretion of an abnormal monoclonal immunoglobulin (paraprotein or M-protein) and prevents the formation of the other antibodies produced by the normal plasma cells that are destroyed. The anormal secretion of paraproteins unbalance the osteoblastosis and osteoclastosis processes, leading to bone lesions that cause lytic bone deposits and the release of calcium from bones (hypercalcemia) that may produce renal failure. Regions affected by bone lesions are the skull, spine, ribs, sternum, pelvis and bones that form part of the shoulders and hips. The substitution of the healthy bone marrow by infiltrating malignant cells and the inhibition of the normal production of red blood cells produce anaemia, thrombocytopenia and leukopenia. Multiple myeloma patients are immunosuppressed because of leukopenia and the abnormal immunoglobulin production caused by the uncontrolled clonal proliferation of plasma cells, being susceptible to bacterial infections, like pneumonias and urinary tract infections. The interaction of immunoglobulin with hemostatic mechanisms may lead to haemorrhagic diathesis or thrombosis. Also, disorders of the central and peripheral nervous system are part of the disease, being the more common neurological manifestations the spinal cord compressions and the peripheral neuropathies.

scholarly journals A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

Leukemia ◽  
2016 ◽  
Vol 31 (8) ◽  
pp. 1743-1751 ◽  
Author(s):  
S Hipp ◽  
Y-T Tai ◽  
D Blanset ◽  
P Deegen ◽  
J Wahl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cell ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Selective Lysis ◽  
Bispecific T Cell Engager

Abstract B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ɛ (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMA-positive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.

scholarly journals Functional Comparison between Healthy and Multiple Myeloma Adipose Stromal Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Nicolas Espagnolle ◽  
Benjamin Hebraud ◽  
Jean-Gérard Descamps ◽  
Mélanie Gadelorge ◽  
Marie-Véronique Joubert ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stromal Cells ◽  
Cellular Therapy ◽  
Plasma Cells ◽  
Bone Lesions ◽  
Adipose Stromal Cells ◽  
Osteolytic Lesions ◽  
Healthy Donors ◽  
Bone Damage ◽  
First Time

Multiple myeloma (MM) is an incurable B cell neoplasia characterized by the accumulation of tumor plasma cells within the bone marrow (BM). As a consequence, bone osteolytic lesions develop in 80% of patients and remain even after complete disease remission. We and others had demonstrated that BM-derived mesenchymal stromal cells (MSCs) are abnormal in MM and thus cannot be used for autologous treatment to repair bone damage. Adipose stromal cells (ASCs) represent an interesting alternative to MSCs for cellular therapy. Thus, in this study, we wondered whether they could be a good candidate in repairing MM bone lesions. For the first time, we present a transcriptomic, phenotypic, and functional comparison of ASCs from MM patients and healthy donors (HDs) relying on their autologous MSC counterparts. In contrast to MM MSCs, MM ASCs did not exhibit major abnormalities. However, the changes observed in MM ASCs and the supportive property of ASCs on MM cells question their putative and safety uses at an autologous or allogenic level.

A Clinically Relevant SCID-hu in Vivo Model of Human Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2455-2455
Author(s):  
Pierfrancesco Tassone ◽  
Paola Neri ◽  
Daniel R. Carrasco ◽  
Renate Burger ◽  
Laurence Catley ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Fluorescence Imaging ◽  
Scid Mice ◽  
In Vivo Model ◽  
Murine Models ◽  
Fetal Bone ◽  
Investigational Drugs ◽  
Human Multiple Myeloma

Abstract Human multiple myeloma (MM) xenografts in immunodeficient mice have limitations as a model for the human disease since they lack the human bone marrow (huBM) microenvironment. In contrast, murine models harboring a huBM microenvironment with implantation of patient MM cells in the huBM recapitulate the in vivo pathophysiology of MM and have significant advantages over conventional murine models for pre-clinical evaluation of investigational drugs. However, there are significant limitations in using patient MM cells in such models since i) not all patient MM samples engraft in the huBM; ii) only a fraction of engrafted specimens produce measurable paraprotein and/or osteolytic lesions; and iii) a limited number of MM cells can be harvested from an individual patient, thus limiting the number of mice that can be injected with cells from the same patient. To overcome these limitations, we have developed a novel murine model of MM by engrafting INA-6, a cytokine-dependent human MM cell line into SCID mice previously implanted with a human fetal bone chip (SCID-hu mice). INA-6 cells require either exogenous IL-6 or interaction with the bone marrow stromal cells (BMSCs) to proliferate in vitro. In this model, we monitored the in vivo growth of INA-6 cells stably transfected with a green fluorescent protein (GFP) expression vector (INA-6GFP+). Serum soluble human IL-6 receptor (shuIL-6R) and fluorescence imaging of host animals were sensitive indicators of tumor burden with time dependent increase. Fluorescence imaging was able to detect the myeloma cell growth earlier than measurement of sIL-6R levels. INA-6 MM cells grew in SCID-hu mice, but not in SCID mice injected subcutaneously or intravenously without the human fetal bone. We have further confirmed the feasibility of this model in monitoring the response to therapeutic agents such as dexamethasone by detecting reduction in the intensity of the fluorescent lesions as well as shuIL-6R in SCID-hu mice following anti-MM treatment. This highly reproducible model therefore allows for evaluation of investigational drugs targeting MM cells in the huBM milieu.

Developing In Vivo Model for Studying Mechanisms of Osteoblast Suppression in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4731-4731
Author(s):  
Chang-Sook Hong ◽  
Alisa Huston ◽  
Flavia Esteve ◽  
Judy Anderson ◽  
Ken Patrene ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Osteoblast Differentiation ◽  
Treated Group ◽  
Bone Lesions ◽  
Neoplastic Disease ◽  
In Vivo Models ◽  
Myeloma Cells ◽  
Ganciclovir Treatment

Abstract Multiple myeloma (MM) is an incurable neoplastic disease characterized by an accumulation of plasma cells in bone marrow. Osteolytic bone lesions are the major source of morbidity in MM patients and are associated with bone pain and fractures and hypercalcemia. The bone lesions result from increased osteoclastic bone destruction in areas adjacent to the myeloma cells. New bone formation that normally happens at sites of previous bone resorption still occurs in early stages of the disease but is absent in advanced MM. Although the molecular basis for the increased osteoclastic activity has been intensely investigated, the basis for the decreased osteoblast activity is just beginning to be understood. Recently, inhibitors of WNT signaling pathway, Dickkorpf1 (DKK1) and secreted Frizzle-Related Protein-2 (sFRP2) have been identified as factors involved in osteoblast suppression in MM. In addition, IL-3 and IL-7 are increased in plasma of MM patients and suppress osteoblastogenesis in cell culture models. However, the role of those factors in the osteoblastic activity in MM patients is unclear. Studies in patients are confounded by cytotoxic therapy as well as bisphosphonates, which are standard therapy for MM patients. Therefore, preclinical in vivo models are required to delineate the mechanisms responsible for the profound osteoblast suppression in MM. We have developed a mouse model of myeloma bone disease in which genetically modified myeloma cells can be selectively ablated without the confounding effects of cytotoxic therapies and allows us to tract the growth of MM cells. The 5TGM1 cell line which is the most common version of murine MM, was stably transfected with the thymidine kinase (TK) gene from herpes simplex virus, which permits eradication of myeloma cells with ganciclovir, as well as GFP and luciferase genes to detect the presence of MM cells. One ug/ml ganciclovir treatment in culture results in 100% death of the transfected 5TGM1 cells in 4 days. Importantly, ganciclovir treatment of primary marrow cell cultures had no effect on growth and differentiation of osteoblast and hematopoietic progentitors. Co-culturing of primary marrow cells with 5TGM1 expressing TK has no bystander effect on osteoblast differentiation with ganciclovir treatment. Subcutaneously implanted 5TGM1 cells into SCID mice were eradicated by intraperitoneal injection of 20mg/kg ganciclovir/d for 2 weeks. The dose of ganciclovir did not affect osteoblast differentiation of primary marrow culture from the mice treated with ganciclovir. Then we injected the 5TGM1 cells into tibia of SCID nude mice (n=4 per group). After measuring the increase of serum IgG2b level, half of the mice were treated with ganciclovir for 2 weeks and the other with saline. Our preliminary data show that osteogenic cultures of bone marrow from the ganciclovir treated mice had significantly higher alkaline phosphatase activity than cultures derived from the saline treated group (p=0.03). In addition, the ganciclovir treated mice had tendency of higher trabecular bone volume than the saline-treated group (p=0.08). These results demonstrate that this model should be useful for studying mechanisms of osteoblast suppression in MM.

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