CD117 expression in gammopathies is associated with an altered maturation of the myeloid and lymphoid hematopoietic cell compartments and favorable disease features

Schmidt‐Hieber, Martin; Pérez-Andrés, Martín; Paiva, Bruno; Flores‐Montero, Juan; Pérez, José J.; Gutiérrez, Norma C.; Vidriales, María‐Belén; Matarraz, Sergio; Miguel, Jesús F. San; Órfão, Alberto

doi:10.3324/haematol.2010.031872

Cited by 48 publications

(45 citation statements)

References 20 publications

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“…These observations confirm previous findings at the single patient level, which suggested that absence of CD56 expression in BM clonal PCs would reflect an increased extramedullary spread potential and more aggressive disease, 29 whereas CD117 expression in MM is associated with a favorable outcome 18 potentially related to an enhanced anchor of clonal PCs to BM niches through kit ligand-expressing stromal cells. 30 Our results support this later hypothesis, suggesting that CTCs represent a phenotypic subset of BM myeloma PCs with lower expression of integrin and adhesion molecules and consequently a lower dependence on BM stromal cell niches would have an enhanced capacity to egress into PB. Of note, CD28, CD38, and CD81 were also found to be downregulated in MM CTCs vs paired BM clonal PCs.…”

Section: Discussionsupporting

confidence: 86%

Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile

Paiva

Paíno

Sayagués

et al. 2013

Blood

144

154

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Key Points• Detailed characterization of myeloma circulating tumor cells shows that these represent a unique subpopulation of BM clonal PCs.• Myeloma CTCs are clonogenic, quiescent, and may represent an ancestral clone potentially driven by circadian rhythms.Circulating myeloma tumor cells (CTCs) as defined by the presence of peripheral blood (PB) clonal plasma cells (PCs) are a powerful prognostic marker in multiple myeloma (MM). However, the biological features of CTCs and their pathophysiological role in MM remains unexplored. Here, we investigate the phenotypic, cytogenetic, and functional characteristics as well as the circadian distribution of CTCs vs paired bone marrow (BM) clonal PCs from MM patients. Our results show that CTCs typically represent a unique subpopulation of all BM clonal PCs, characterized by downregulation (P < .05) of integrins (CD11a/CD11c/CD29/CD49d/CD49e), adhesion (CD33/CD56/CD117/CD138), and activation molecules (CD28/CD38/CD81). Fluorescence in situ hybridization analysis of fluorescence-activated cell sorter-sorted CTCs also unraveled different cytogenetic profiles vs paired BM clonal PCs. Moreover, CTCs were mostly quiescent and associated with higher clonogenic potential when cocultured with BM stromal cells. Most interestingly, CTCs showed a circadian distribution which fluctuates in a similar pattern to that of CD34 1 cells, and opposite to stromal cell-derived factor 1 plasma levels and corresponding surface expression of CXC chemokine receptor 4 on clonal PCs, suggesting that in MM, CTCs may egress to PB to colonize/metastasize other sites in the BM during the patients' resting period. (Blood. 2013;122(22):3591-3598) IntroductionIn the late 2000s, 2 pivotal studies elegantly showed that monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM) in most, if not all myeloma patients. 1,2End-organ damage is the most important criterion to classify therapyrequiring MM patients, and the most common CRAB (hyperCalcemia, Renal failure, Anemia, Bone lesions) symptom is the presence of bone lesions detectable on a skeletal survey.3 Extramedullary disease is present in ;10% of newly diagnosed symptomatic patients, but it increases up to 20% in the relapse/refractory setting, 4 and typically anticipates a dismal outcome. Plasma cell (PC) leukemia is one of the most aggressive forms of the disease and even with novel drugs, the outcome is very poor with both short remission and survival rates.5 This landscape does not greatly differ from that of most solid tumors, in which the presence of metastasis is a key prognostic factor. 6 In fact, recent observations suggest that tumor cell dissemination is often an early event, 7 and the clinical sequel of circulating tumor cells (CTCs) has been the focus of extensive research. 8Interestingly, peripheral blood (PB) MM CTCs (morphologic and phenotypically defined as mature PCs) are also a common event throughout the spectrum of MM. [9][10][11][12][13] CTCs can only be detected in a small fraction of newly diagn...

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Section: Discussionsupporting

confidence: 86%

Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile

Paiva

Paíno

Sayagués

et al. 2013

Blood

144

154

View full text Add to dashboard Cite

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“…25,27 Briefly, translocations involving the IGH gene at chromosome 14q32 and either del(14q32) or +14q32 in the absence of t(14q32) were identified with a panel of standard LSI IGH dual-color break-apart rearrangement probes purchased from Vysis (Downers Grove, IL, USA). Samples showing an IGH gene rearrangement or del(14q32) potentially associated with an IGH gene rearrangement (one fusion and one split signal) were further analyzed using specific fusion probes for the most frequent t(14q32) chromosomal translocations -e.g, t(4;14), t (11;14), and t(14;16) -(Vysis).…”

Section: Interphase Fluorescence In Situ Hybridization Studiesmentioning

confidence: 99%

Cytogenetic profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: a study in highly purified aberrant plasma cells

et al. 2012

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Cytogenetic studies in clonal plasma cell disorders have mainly been done in whole bone marrow or CD138 + microbead-enriched plasma cells and suggest that recurrent immunoglobulin heavy chain translocations -e.g. t(4;14) -are primary oncogenetic events. The aim of this study was to determine cytogenetic patterns of highly purified aberrant plasma cells (median purity ≥98%) in different clonal plasma cell disorders. We analyzed aberrant plasma cells from 208 patients with multiple myeloma (n=148) and monoclonal gammopathy of undetermined significance (n=60) for the presence of del(13q14), del(17p13) and t(14q32) using multicolor interphase fluorescence in situ hybridization. Additionally, immunoglobulin heavy chain gene arrangements were analyzed and complementarity determining region 3 was sequenced in a subset of patients and combined multicolor interphase fluorescence in situ hybridization/immunofluorescent protein staining analyses were performed in selected cases to confirm clonality and cytogenetic findings. At diagnosis, 96% of cases with multiple myeloma versus 77% of monoclonal gammopathy of undetermined significance cases showed at least one cytogenetic alteration and/or hyperdiploidy. The cytogenetic heterogeneity of individual cases reflected coexistence of cytogenetically-defined aberrant plasma cell clones, and led to the assumption that karyotypic alterations were acquired stepwise. Cases of multiple myeloma and monoclonal gammopathy of undetermined significance frequently showed different but related cytogenetic profiles when other cytogenetic alterations such as deletions/gains of the immunoglobulin heavy chain or the fibroblast growth factor receptor 3 were additionally considered. Interestingly, in 24% of multiple myeloma versus 62% of monoclonal gammopathy of undetermined significance patients with an immunoglobulin heavy chain translocation, aberrant plasma cells with and without t(14q32) coexisted in the same patient. Our data suggest that recurrent immunoglobulin heavy chain translocations might be absent in the primordial plasma cell clone in a significant proportion of patients with clonal plasma cell disorders carrying these cytogenetic alterations.

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“…11,[19][20][21] In myeloma, it could be hypothesized that due to occupation of BM niches by clonal PC, normal BM cells are expelled from their natural microenvironment, 22 translating into deregulated hematopoiesis. 23 If this is the case, it would be expected that due to increasing tumor burden, the frequency and extent of phenotypic alterations would be slightly higher in newly diagnosed symptomatic patients than in high-risk SMM patients. However, detailed immunophenotypic analysis of the different hematopoietic BM cell compartments revealed no significant differences in the frequency of altered CD34 Table 1.…”

Section: Resultsmentioning

confidence: 99%

Myelodysplasia-associated immunophenotypic alterations of bone marrow cells in myeloma: are they present at diagnosis or are they induced by lenalidomide?

et al. 2012

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CD117 expression in gammopathies is associated with an altered maturation of the myeloid and lymphoid hematopoietic cell compartments and favorable disease features

Cited by 48 publications

References 20 publications

Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile

Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile

Cytogenetic profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: a study in highly purified aberrant plasma cells

Myelodysplasia-associated immunophenotypic alterations of bone marrow cells in myeloma: are they present at diagnosis or are they induced by lenalidomide?

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