Molecular Biclonality: Analysis of Clonotypic IgH VDJ Reveals the Frequent Occurrence of a Second Clone in Multiple Myeloma.
Notice bibliographique
Résumé
Abstract Abstract 1813 Poster Board I-839 Malignant clones in multiple myeloma (MM) express unique clonotypic VDJ sequences associated with the clinical isotype. It has been widely assumed that MM patients have only one clone. However, our analysis reveals that a high frequency of MM patients have two clones. Analysis of complementary determining region 3 (CDR3) in bone marrow (BM) by DNA fragment analysis using florescent labeled consensus primers that bind to the framework region 3 and the joining region (FR3/JHc) or the framework region 3 and the constant region (FR3/CH1) related to the clinical isotype typically yields a single CDR3 peak, corresponding to the clonotypic VDJ gene segments. Signature sequences identified from CDR2 and CDR3 of clonotypic VDJ provides a molecular tool to monitor the malignant clone within a given patient. Study of CDR3 in BM and peripheral blood (PB) provides valuable information about the IgH VDJ repertoire and Ig expression profile, especially in cases where two clonal sequences are molecularly identified or when validation by single cell analysis did not show high frequency for a presumptive clonotypic IgH VDJ. Here, we analysed CDR3 expression profile in 23 MM patients. The results indicated a high incidence of MM having a second clone (6/23 patients, 26%). Reverse transcription-polymerase chain reaction (RT-PCR) of FR3/JHc and FR3/CH1 reveals a CDR3 peak representing the major MM clone in all 23 BM analysed. Among 23 patients, 6 (4 IgG, 2 IgA) exhibit a second monoclonal peak which can be detected both in PB and BM. Fluorescent in situ hybridization was unable to detect an increased incidence of IgH translocations within these 6 patients. Characterization of VDJ sequences indicated that the second clone mainly utilizes VH3 gene family (5/6), undergoes somatic hypermutation (5/6 at 2% cutoff) and does not derive from MM clone (6/6) as shown by different combinatorial and junctional diversity. Repertoire analysis determined by FR3/JHc amplification of genomic DNA excluded biallelic expression of the MM clone. In patient MM1, the second clone (μ) predominates in PB while the MM clone (γ) predominates in BM. In MM2, the second clone has a very short CDR3 (18 nt), predominates in blood compartment and has undergone isotype switching (μ, γ, á). In MM3, the M protein is of IgG type, consistent with transcripts in an FR3/Cγ RT-PCR peak in BM, but repertoire analysis of genomic DNA showed that the majority of B lineage cells in bone marrow and blood have a rearranged μ isotype. In MM4, having a homogeneous MM (á) clone, the second clone (á) exhibited intraclonal diversity, as defined by sequencing of VDJ subclones. In MM5, clonal transcripts of both dominant γ clone and the second clone (á) persisted in blood following initial chemotherapy. In MM6, the MM clone (γ) predominates over the second clone (á) both in BM and PB. Overall, our studies indicate a high incidence of biclonal expansion in MM. The unrelated VDJ origin of sister clones detected in MM patients exhibiting biclonality suggests that they may have arisen from different transformation event, which may be promoted when cumulative genetic abnormalities reach a critical threshold. Although clinical manifestations in a patient may reflect a take-over by the most aggressive clone, our studies suggest that transformation may be an ongoing event that occurs at a heretofore underestimated rate in MM B lineage cells. Disclosures No relevant conflicts of interest to declare.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».