Evaluation of NCAM and DKK1 Expression in Multiple Myeloma and MGUS by Gene and Tissue Microarrays: Expression Accompanies Progression.

Abstract Introduction: Expression NCAM1, a cell adhesion molecule involved in neuron-neuron adhesion, is also expressed by multiple myeloma (MM PC). Osteolytic bone lesions are a hallmark of MM and elevated expression of NCAM in MM PC has been correlated with this process (Ely and Knowles, 2003). We have previously reported that MM PC express DKK1 and MM blocks osteoblast differentiation in a DKK1-specific manner, suggesting that secretion of the Wnt signaling inhibitor plays a role in MM bone disease. Herein we used gene expression microarrays and tissue microarrays (TMAs) to investigate the simultaneous expression of DKK1 and NCAM in MM and MGUS. Methods: The study population consisted of 198 newly diagnosed MM and 44 MGUS. RNA from CD138-selected plasma cells was hybridized to Affymetrix U133Plus microarrays and data processed with Affymetrix Microarray Suite GCOS1.1 software. TMAs were constructed from formalin-fixed, paraffin embedded bone marrow biopsies. Serial sections of TMA were immunostained for CD138, NCAM and DKK1. TMAs were scanned using ScanScope using 20x lens, assessed using TMA lab software (Aperio Technologies) and scored as an average number of cells in the context of CD138 staining. Results: When put in context of a recently described molecular classification (Zhan et al., 2006), NCAM and DKK1 were found significantly co-over-expressed (DKK1+/NCAM+) in HYPERDIPLOID MM (P < 0.01); NCAM+/DKK1− was typical for MMSET-spike MM (P<0.001); NCAM−/DKK1+ DKK1 was characteristic of MM in MAF-spike disease (P < 0.001), CCND1 spikes with co-expression of CD20 (P<0.01), and the so-called MYELOID subgroup (P<0.001). In contrast, virtually all cases of MGUS were DKK1−/NCAM-. On TMAs, DKK1 expression varied in CD138-positive cells in MM, and in osteocytes and megakaryocytes in MM and MGUS, but was clearly negative in osteoblasts/lining cells. NCAM expression, was also variably expressed in PC of MM cases and in virtually 100% of osteoblasts/lining cells in both MM and MGUS. Osteocytes were distinctly negative for NCAM in both diseases. Of 195 analyzable MM biopsies, PC were DKK1+ in 1% to > 90% of PC in 191 (98%); of these, 94 were also NCAM+ in 5% to > 90% of PC; 1 case was positive for NCAM+/DKK− and 3 were NCAM−/DKK−. There was no significant difference in clinical parameters and survival in a comparison of NCAM+/DKK+ and NCAM−/DKK+ groups. DKK1 gene expression was higher in DKK1+/NCAM+ than in DKK1+/NCAM− MM (P=0.006); NCAM gene expression was higher in DKK1+/NCAM+ than in DKK+/NCAM− MM (P<0.0001) and NCAM was the number one SAM-defined gene over-expressed in DKK1+/NCAM+ relative to DKK1+/NCAM− disease. Consistent with GEP data, DKK1+/NCAM+ MM was over-represented in HYPERDIPLOID MM (32% v. 10%; P<0.001), while DKK1+/NCAM− disease was overrepresented in MAF-spike (15% v. 2%; P=0.003) and MYELOID subgroups (32% v. 18%; P=0.03). DKK1+/NCAM+ MM was completely absent in CCND1-spike /CD20-negative disease, with only 4% of DKK1+/NCAM− cases in this subgroup. No difference was observed for the other subtypes. Conclusion: DKK1 is expressed in all cases of MM with half also expressing NCAM. Neither gene is expressed in MGUS PC. These data suggests that expression of these genes in plasma cells accompanies disease progression.

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Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients

Blood ◽

10.1182/blood-2009-12-261032 ◽

2010 ◽

Vol 116 (14) ◽

pp. 2543-2553 ◽

Cited By ~ 171

Author(s):

Annemiek Broyl ◽

Dirk Hose ◽

Henk Lokhorst ◽

Yvonne de Knegt ◽

Justine Peeters ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Plasma Cells ◽

Medical Science ◽

Protein Tyrosine Phosphatases ◽

Molecular Classification ◽

Newly Diagnosed ◽

Expression Of Genes

Abstract To identify molecularly defined subgroups in multiple myeloma, gene expression profiling was performed on purified CD138+ plasma cells of 320 newly diagnosed myeloma patients included in the Dutch-Belgian/German HOVON-65/GMMG-HD4 trial. Hierarchical clustering identified 10 subgroups; 6 corresponded to clusters described in the University of Arkansas for Medical Science (UAMS) classification, CD-1 (n = 13, 4.1%), CD-2 (n = 34, 1.6%), MF (n = 32, 1.0%), MS (n = 33, 1.3%), proliferation-associated genes (n = 15, 4.7%), and hyperdiploid (n = 77, 24.1%). Moreover, the UAMS low percentage of bone disease cluster was identified as a subcluster of the MF cluster (n = 15, 4.7%). One subgroup (n = 39, 12.2%) showed a myeloid signature. Three novel subgroups were defined, including a subgroup of 37 patients (11.6%) characterized by high expression of genes involved in the nuclear factor kappa light-chain-enhancer of activated B cells pathway, which include TNFAIP3 and CD40. Another subgroup of 22 patients (6.9%) was characterized by distinct overexpression of cancer testis antigens without overexpression of proliferation genes. The third novel cluster of 9 patients (2.8%) showed up-regulation of protein tyrosine phosphatases PRL-3 and PTPRZ1 as well as SOCS3. To conclude, in addition to 7 clusters described in the UAMS classification, we identified 3 novel subsets of multiple myeloma that may represent unique diagnostic entities.

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MyPRSR Molecular Subtypes of Multiple Myeloma Represent All High-Risk FISH Translocations Included in the mSMART 2.0 and R-ISS Guidelines

Blood ◽

10.1182/blood.v128.22.3264.3264 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3264-3264 ◽

Cited By ~ 1

Author(s):

Ryan K Van Laar ◽

Ivan Borrelo ◽

David Jabalayan ◽

Ruben Niesvizky ◽

Aga Zielinski ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

High Risk ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Research Funding ◽

Plasma Cells ◽

Molecular Subtypes ◽

Risk Status ◽

Significant Difference

Abstract Background: There is a global consensus that multiple myeloma patients with high-risk disease require additional monitoring and therapy compared to low/standard risk patients in order to maximize their chances of survival. Current diagnostic guidelines recommend FISH-based assessment of chromosomal aberrations to determine risk status (i.e. t(14;20), t(14;16), t(4;14) and/or Del17p), however, studies show FISH for MM may have a 20-30% QNS rate and is up to 15% discordant between laboratories, even when starting from isolated plasma cells. In this study we demonstrate that MyPRS gene expression profiling reproduces the key high risk translocations for MM risk stratification, in addition to having other significant advantages. Methods: Reproducibility studies show that MyPRS results are less than 1% discordant starting from isolated plasma cells and return successful results in up to 95% of cases. 270 MM patients from Johns Hopkins University (MD) and Weill Cornell Medicine (NY) had both FISH and MyPRS gene expression profiling performed between 2012 and 2016 using standard and previously published methodology, respectively. Results: Retrospective review of the matched FISH and MyPRS results showed: 25/28 (89%) patients wish FISH-identified t(4;14) were classified as MMSET (MS) subtype. 10/10 (100%) patients with t(14;16) or t(14;20) were classified as MAF-like (MF) subtype 62/67 (93%) patients with t(11;14) were assigned to the Cyclin D (1 or 2) subtype. Patients with FISH hyperdiploidy status were classified as the Hyperdiploid (HY) subtype or had multiple gains detected by the separate MyPRS Virtual Karyotype (VK) algorithm, included in MyPRS. TP53del was seen in patients with multiple molecular subtypes, predominantly Proliferation (PR) and MMSET (MS). Assessment of TP53 function by gene expression is a more clinically relevant prognostic marker than TP53del, as dysregulation of the tumor suppressor is affected by mutations as well as deletions. Analysis of the TP53 expression in the 39 patients with delTP53 showed a statistically significant difference, compared to patients without this deletion (P<0.0001). Conclusion: Gene expression profiling is a superior and more reliable method for determining an individual patients' prognostic risk status. The molecular subtypes of MM, as reported by Signal Genetics MyPRS assay, are driven by large-scale changes in gene expression caused by or closely associated with chromosomal changes, including translocations. Physicians who are managing myeloma patients and wishing to base their assessment of risk on R-ISS or mSMART Guidelines may obtain the required data points from either FISH or MyPRS, with the latter offering lower QNS rates, higher reproducibility, assessment of a larger number of cells and a substantially lower price point ($5,480 vs. $1,912; 2016 CMS data). A larger cohort study is now underway to further validate these observations. Figure GEP-based TP53 expression in patients with and without Del17p. P<0.0001 Figure. GEP-based TP53 expression in patients with and without Del17p. P<0.0001 Disclosures Van Laar: Signal Genetics, Inc.: Employment. Borrelo:Sidney Kimmel Cancer Institute: Employment. Jabalayan:Weill Cornell Medical Center: Employment. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau. Zielinski:Signal Genetics, Inc.: Employment. Leigh:Signal Genetics, Inc.: Employment. Brown:Signal Genetics, Inc.: Employment. Bender:Signal Genetics, Inc.: Employment.

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High Levels of APOBEC3B Gene Expression Contribute to Poor Prognosis in Multiple Myeloma Patients

Blood ◽

10.1182/blood-2018-99-117067 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3897-3897

Author(s):

Valeriy V Lyzogubov ◽

Pingping Qu ◽

Cody Ashby ◽

Adam Rosenthal ◽

Antje Hoering ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Poor Prognosis ◽

Target Genes ◽

Plasma Cells ◽

Nuclear Fraction ◽

Advisory Committees ◽

Significant Difference

Abstract Introduction: Poor prognosis and drug resistance in multiple myeloma (MM) is associated with increased mutational load. APOBEC3B is a major contributor to mutagenesis, especially in myeloma patients with t(14;16) MAF subgroup. It was shown recently that presence of the APOBEC signature at diagnosis is an independent prognostic factor for progression free survival (PFS) and overall survival (OS). We hypothesized that high levels of APOBEC3B gene expression at diagnosis may also have a prognostic impact in myeloma. To consider APOBEC3B as a potential target for therapy more studies are necessary to understand how APOBEC3B expression is regulated and how APOBEC3B generates mutations. Methods: Gene expression profiling (GEP, U133 Plus 2.0) of MM patients was performed. APOBEC3B gene expression levels were investigated in plasma cells of healthy donors (HD; n=34), MGUS (n=154), smoldering myeloma (SMM; n=219), MM low risk (LR; n=739), MM high risk (HR; n=129), relapsed MM (RMM; n=74), and primary plasma cell leukemia (pPCL; n=19) samples. The samples from relapse were taken on or after the progression/relapse date but within 30 days after progression/relapse from Total Therapy trials 3, 4, 5 & 6. GEP70 score was used to separate samples into LR and HR groups. We also investigated APOBEC3B expression in different MM molecular subgroups and used logrank statistics with covariate frequency distribution to determine an optimal cut off APOBEC3B expression value. Gene expression was compared in cases with low expression of APOBEC3B (log2<7.5) and high expression of APOBEC3B (log2>10), and an optimal cut-point in APOBEC3B expression was identified with respect to PFS. To explore the role of MAF and the non-canonical NF-ĸB pathway we performed functional studies using a cellular model of MAF downregulation. TRIPZ lentiviral shRNA MAF knockdown in the RPMI8226 cell lines was used to explore MAF-dependent genes. NF-ĸB proteins, p52 and RelB, were investigated in the nuclear fraction by immunoblot analysis. Results: Expression of APOBEC3B in HD control samples (log2=10.9) was surprisingly higher than in MGUS (log2=9.51), SMM (log2=9.09), and LR (log2=9.40) and was comparable to HR (log2=10.4) and RMM (log2=10.6) groups. Expression levels of APOBEC3B were gradually increased as disease progressed from SMM to pPCL. The high expression of APOBEC3B in HD places plasma cells at risk of APOBEC induced mutagenesis where the regulation of APOBEC3B function is compromised. The correlation between APOBEC3B expression and GEP70 score in MM was 0.37, and there was a significant difference in APOBEC3B expression between GEP70 high and low risk groups (p=0.0003). An optimal cut-point in APOBEC3B expression of log2=10.2 resulted in a significant difference in PFS (median 5.7 yr vs.7.4 yr; p=0.0086) and OS (median 9.1 yr vs. not reached; p<0.0001), between high and low expression. The highest APOBEC3B expression was detected in cases with a t(14;16). We analyzed t(14;16) cases with the APOBEC mutational signature and compared them to t(14;16) cases without the APOBEC signature and found elevated MAF (2-fold) and APOBEC3B (2.7-fold) gene expression in samples with the APOBEC signature. No APOBEC signature was detected in SMM cases, including those with a t(14;16). High APOBEC3B levels in myeloma patients was associated with overexpression of genes related to response to DNA damage and cell cycle control. Significant (p<0.05) increases of NF-κB target genes was seen in high APOBEC3B cases: TNFAIP3 (4.4-fold), NFKB2 (1.7-fold), NFKBIE (1.9-fold), RELB (1.4-fold), NFKBIA (2.0-fold), PLEK (2.5-fold), MALT1 (2.5-fold), WNT10A (2.4-fold). However, in t(14;16) cases there was no significant increase of NF-κB target genes except BIRC3 (2.5-fold) and MALT1 (2.0-fold). MAF downregulation in RPMI8226 cells did not lead to changes in NF-κB target gene expression but MAF-dependent genes were identified, including ETS1, SPP1, RUNX2, HGF, IGFBP2 and IGFBP3. Analysis of nuclear fraction of NF-ĸB proteins did not show significant changes in expression of p52 and RelB in RPMI8226 cells after MAF downregulation. Conclusions: Increased expression of APOBEC3B is a negative prognostic factor in multiple myeloma. MAF is a major factor regulating expression of APOBEC3B in the t(14;16) subgroup. NF-ĸB pathway activation is most likely involved in upregulation of APOBEC3B in non-t(14;16) subgroups. Disclosures Davies: TRM Oncology: Honoraria; MMRF: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ASH: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria.

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Molecular Profiling of Extramedullary and Medullary Plasmacytomas Compared to Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.4042.4042 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4042-4042

Author(s):

Anuj Mahindra ◽

Samir B. Amin ◽

Aliyah R. Sohani ◽

Gabriela Motyckova ◽

Kishan Patel ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Plasma Cell ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Expression Patterns ◽

Metastatic Potential ◽

Tissue Microarrays ◽

Molecular Characteristics ◽

New Therapeutic Approaches

Abstract Abstract 4042 Plasmacytomas are rare clonal proliferations of plasma cells that though cytologically identical to plasma cell myeloma, present with osseous or extraosseous growth pattern. Understanding their molecular characteristics can provide crucial insights into their pathogenesis and risk of progression to multiple myeloma (MM). To investigate the differences between extramedullary (EMP) and medullary plasmacytomas (MP) and MM without plasmacytomas, we sought to molecularly profile these tumors by tissue microarrays, gene expression, microRNA, and FISH. We identified 85 patients from our data base with a pathological diagnosis of plasmacytoma. Of the 85 patients, 13 patients presented with EMP, and 72 had MP. Among the patients with EMP (n=13), 2 patients presented with multiple lesions. Three of 13 (23%) patients progressed to develop MM at a median of 12 months. 72 patients presented with MP, of which 21 had solitary lesions and 27 (37%) progressed to MM at a median of 20.5months. There was a male preponderance (67% vs 33%) and the median age at diagnosis was 60.5 years (range 27.7–87.6). The mean overall survival for patients with EMP was 121 months (95% confidence interval[CI] 97–144 months) and for patients with MP was 102 months (95% CI 93–128 months) {p=0.025}. MicroRNA (miRNAs) profiling was performed on MP (n=19), EMP (n=7) and MM samples (n=66). Data was normalized using U6 endogenous control. Gene expression profiling was performed and correlated with the miRNA data to identify genes and transcripts of interest. miRNA 127, which regulates SET D8, was upregulated four fold in both MP and EMP compared to MM. miRNA 493, which regulates cadherin 11 and PTCH 1, both of which have been associated with metastatic potential in solid tumors, was similarly downregulated four fold in both MP and EMP compared to MM. A tissue microarray was created on 52 patients (8: EMP, 44: MP,) in whom paraffin-embedded tissue was available. Additional evaluation using SET 8, cadherin 11 antibodies and validation of additional functional targets is ongoing and will be reported. Differential expression patterns of factors involved in proliferation, survival, adhesion, and stroma-tumor cell interactions may help explain plasmacytoma biology and identify factors responsible for progression to MM. These insights may help identify new therapeutic approaches and targets in the treatment of these plasma cell disorders. Disclosures: No relevant conflicts of interest to declare.

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Bone disease as the first manifestation of systemic AL-amyloidosis

Terapevticheskii arkhiv ◽

10.26442/00403660.2020.07.000775 ◽

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.

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Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Oncogene ◽

10.1038/s41388-020-01590-8 ◽

2021 ◽

Author(s):

Yinyin Xu ◽

Jing Guo ◽

Jing Liu ◽

Ying Xie ◽

Xin Li ◽

...

Keyword(s):

Multiple Myeloma ◽

Combined Treatment ◽

Hypoxia Inducible Factor ◽

Bone Destruction ◽

Bone Lesions ◽

Myeloma Cells ◽

Downstream Target ◽

Dkk1 Expression

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

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The oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells

Blood ◽

10.1182/blood-2006-11-056747 ◽

2007 ◽

Vol 109 (10) ◽

pp. 4470-4477 ◽

Cited By ~ 61

Author(s):

Simona Colla ◽

Fenghuang Zhan ◽

Wei Xiong ◽

Xiaosong Wu ◽

Hongwei Xu ◽

...

Keyword(s):

Oxidative Stress ◽

Multiple Myeloma ◽

Wnt Signaling ◽

Plasma Cells ◽

Cell Types ◽

Signaling Cascade ◽

Jnk Pathway ◽

Jnk Signaling ◽

Dkk1 Expression

Abstract Multiple myeloma (MM) plasma cells, but not those from healthy donors and patients with monoclonal gammopathy of undetermined significance or other plasma cell dyscrasias involving the bone marrow, express the Wnt-signaling antagonist DKK1. We previously reported that secretion of DKK1 by MM cells likely contributes to osteolytic lesions in this disease by inhibiting Wnt signaling, which is essential for osteoblast differentiation and survival. The mechanisms responsible for activation and regulation of DKK1 expression in MM are not known. Herein, we could trace DKK1 expression changes in MM cells to perturbations in the JNK signaling cascade, which is differentially modulated through oxidative stress and interactions between MM cells with osteoclasts in vitro. Despite its role as a tumor suppressor and mediator of apoptosis in other cell types including osteoblasts, our data suggest that DKK1, a stress-responsive gene in MM, does not mediate apoptotic signaling, is not activated by TP53, and its forced overexpression could not inhibit cell growth or sensitize MM cells to apoptosis following treatment with thalidomide or lenalidomide. We conclude that specific strategies to modulate persistent activation of the JNK pathway may be beneficial in preventing disease progression and treating myeloma-associated bone disease by inhibiting DKK1 expression.

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

Case Reports in Hematology ◽

10.1155/2018/7863943 ◽

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.

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

Edelweiss: Cancer Open Access ◽

10.33805/2689-6737.101 ◽

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.

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Functional Comparison between Healthy and Multiple Myeloma Adipose Stromal Cells

Stem Cells International ◽

10.1155/2020/4173578 ◽

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.

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