PS1131 HIGH‐THROUGHPUT B‐CELL IMMUNOPROFILING AT DIAGNOSIS AND RELAPSE OFFERS FURTHER EVIDENCE OF FUNCTIONAL SELECTION THROUGHOUT THE NATURAL HISTORY OF CHRONIC LYMPHOCYTIC LEUKEMIA
Anna VardiElisavet VlachonikolaS. MouratiFotis PsomopoulosN. PantouloufosAnastasia KouvatsiNiki StavroyianniΑchilles AnagnostopoulosΚώστας ΣταματόπουλοςAnastasia Hadzidimitriou
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Background: Chronic lymphocytic leukemia (CLL) is divided into two broad prognostic categories, namely mutated (M) and unmutated (U) CLL, according to the somatic hypermutation (SHM) status of the clonotypic heavy chain immunoglobulin (IGHV) gene. This is perceived to remain stable over time, as evidenced by low‐throughput studies, which however precluded investigation of subclonal architecture and evolution overtime. Aims: Here, we sought to comprehensively assess the B cell receptor (BcR) IG gene repertoire at CLL diagnosis and 1 st relapse after chemoimmunotherapy (FCR) by next‐generation sequencing (NGS). Methods: We studied 5 patients, of whom 1 each expressed BcR IG typical of stereotyped subset #1 (U‐CLL), subset #4 (M‐CLL) or subset #6 (U‐CLL), whereas the remaining 2 concerned non‐stereotyped U‐CLL. Genomic DNA was amplified by multiplex PCR and products were subjected to paired‐end NGS. Sequence data were processed by a validated bioinformatics pipeline performing strict quality filtering. Rearrangements with identical IGHV gene and CDR3 amino acid (aa) sequence were defined as clonotypes. The dominant clonotype was defined as major, and clonotypes with the same IGHV gene, CDR3 length, and ≤2 aa differences within the CDR3 were considered as its satellite subclones. Results: In total, we analyzed 1,682,728 filtered‐in, productive IGHV‐IGHD‐IGHJ gene rearrangements (median 195,460 rearrangements/sample). In all cases, the major clonotype (IGHV and CDR3 aa sequence) was identical to that determined by Sanger sequencing and remained the same at diagnosis and relapse. However, it consisted of multiple distinct nucleotide (nt) sequences; while most nt sequences displayed the same SHM load as with Sanger (median 73.9% of all nt sequences of the major clonotype), there were other nt sequences with higher or lower SHM load. In all cases, nt sequences with discordant SHM status were practically negligible (median frequency 0.01%). Notably, the relative frequency of the dominant nt sequence increased at relapse for all cases (median increase by 3.7%, p < 0.01). A particular note for subset #4, which by definition displays high SHM, was the emergence of major clonotype nt sequences with lower or even absent SHM at relapse. The median frequency of the major clonotype at diagnosis was 92.5% (range 86.1–93.3%) and remained stable at relapse (92.6%, range 89.9–93.8%). In all cases, the major clonotype came along with numerous satellite subclones (same IGHV gene, CDR3 length, and ≤2 aa differences within the CDR3) at both diagnosis and relapse (median n = 685 vs n = 604 respectively, p>0.05). When considering both the major clonotype and its satellite subclones, the respective cumulative frequency corresponded to nearly the entire B cell repertoire/sample (median 99.6%, range 97.6–99.8%). Subset #4 satellite sublones displayed recurrent SHM patterns within the CDR3 at relapse, which actually diverged from the major clonotype and converged towards the consensus CDR3 sequence for this subset as defined by 176 different subset #4 patients. Summary/Conclusion: Overall, our study provides insight into the evolving architecture of the BcR IG repertoire of relapsing CLL, revealing that, similar to genomic subclones, there is a universe of BcR IG subclones as well. While the possibility of technical error cannot be excluded, the identification of recurrent SHM patterns and trends at relapse strongly points towards functional selection.Keywords:
IGHV@
breakpoint cluster region
Immunoglobulin heavy chain
IGHD
Sanger sequencing
Analyses of IGHV gene mutations in chronic lymphocytic leukemia (CLL) have had a major impact on the prognostication and treatment of this disease. A hallmark of IGHV-mutation status is that it very rarely changes clonally over time. Nevertheless, targeted and deep DNA sequencing of IGHV-IGHD-IGHJ regions has revealed intraclonal heterogeneity. We used a DNA sequencing approach that achieves considerable depth and minimizes artefacts and amplification bias to identify IGHV-IGHD-IGHJ subclones in patients with prolonged temporal follow-up. Our findings extend previous studies, revealing intraclonal IGHV-IGHD-IGHJ diversification in almost all CLL clones. Also, they indicate that some subclones with additional IGHV-IGHD-IGHJ mutations can become a large fraction of the leukemic burden, reaching numerical criteria for monoclonal B-cell lymphocytosis. Notably, the occurrence and complexity of post-transformation IGHV-IGHD-IGHJ heterogeneity and the expansion of diversified subclones are similar among U-CLL and M-CLL patients. The molecular characteristics of the mutations present in the parental, clinically dominant CLL clone (CDC) differed from those developing post-transformation (post-CDC). Post-CDC mutations exhibit significantly lower fractions of mutations bearing signatures of activation induced deaminase (AID) and of error-prone repair by Polη, and most of the mutations were not ascribable to those enzymes. Additionally, post-CDC mutations displayed a lower percentage of nucleotide transitions compared with transversions that was also not like the action of AID. Finally, the post-CDC mutations led to significantly lower ratios of replacement to silent mutations in VH CDRs and higher ratios in VH FRs, distributions different from mutations found in normal B-cell subsets undergoing an AID-mediated process. Based on these findings, we propose that post-transformation mutations in CLL cells either reflect a dysfunctional standard somatic mutational process or point to the action of another mutational process not previously associated with IG V gene loci. If the former option is the case, post-CDC mutations could lead to a lesser dependence on antigen dependent BCR signaling and potentially a greater influence of off-target, non-IG genomic mutations. Alternatively, the latter activity could add a new stimulatory survival/growth advantage mediated by the BCR through structurally altered FRs, such as that occurring by superantigen binding and stimulation.
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We analyzed the CDR3 region of 80 children with B-cell acute lymphoblastic leukemia (B-ALL) using the ImMunoGeneTics Information System and JOINSOLVER. In total, 108 IGH@ rearrangements were analyzed. Most of them (75.3%) were non-productive. IGHV@ segments proximal to IGHD–IGHJ@ were preferentially rearranged (45.3%). Increased utilization of IGHV3 segments IGHV3-13 (11.3%) and IGHV3-15 (9.3%), IGHD3 (30.5%), and IGHJ4 (34%) was noted. In pro-B ALL more frequent were IGHV3-11 (33.3%) and IGHV6-1 (33.3%), IGHD2-21 (50%), IGHJ4 (50%), and IGHJ6 (50%) segments. Shorter CDR3 length was observed in IGHV@6, IGHD7, and IGHJ1 segments, whereas increased CDR3 length was related to IGHV3, IGHD2, and IGHJ4 segments. Increased risk of relapse was found in patients with productive sequences. Specifically, the relapse-free survival rate at 5 years in patients with productive sequences at diagnosis was 75% (standard error [SE] ±9%), whereas in patients with non-productive sequences it was 97% (SE ±1.92%) (p-value = 0.0264). Monoclonality and oligoclonality were identified in 81.2% and 18.75% cases at diagnosis, respectively. Sequence analysis revealed IGHV@ to IGHDJ joining only in 6.6% cases with oligoclonality. The majority (75%) of relapsed patients had monoclonal IGH@ rearrangements. The preferential utilization of IGHV@ segments proximal to IGHDJ depended on their location on the IGHV@ locus. Molecular mechanisms occurring during IGH@ rearrangement might play an essential role in childhood ALL prognosis. In our study, the productivity of the rearranged sequences at diagnosis proved to be a significant prognostic factor.
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Immunoglobulin heavy chain
IGHD
Gene rearrangement
clone (Java method)
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Classification of patients with chronic lymphocytic leukemia (CLL) based on the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene has established predictive and prognostic relevance. The SHM status is assessed based on the number of mutations within the IG heavy variable domain sequence, albeit only over the rearranged IGHV gene excluding the variable heavy complementarity determining region 3 (VH CDR3). This may lead to an underestimation of the actual impact of SHM, in fact overlooking the most critical region for antigen-antibody interactions, i.e. the VH CDR3. Here we investigated whether SHM may be present within the VH CDR3 of cases bearing 'truly unmutated' IGHV genes (i.e. 100% germline identity across VH FR1-VH FR3) employing Next Generation Sequencing. We studied 16 patients bearing a 'truly unmutated' CLL clone assigned to stereotyped subsets #1 (n=12) and #6 (n=4). We report the existence of SHM within the germline-encoded 3'IGHV, IGHD, 5'IGHJ regions of the VH CDR3 in both the main IGHV-IGHD-IGHJ gene clonotype and its variants. Recurrent somatic mutations were identified between different patients of the same subset, supporting the notion that they represent true mutational events rather than technical artefacts; moreover, they were located adjacent to/within AID hotspots, pointing to SHM as the underlying mechanism. In conclusion, we provide immunogenetic evidence for intra-VH CDR3 variations, attributed to SHM, in CLL patients carrying 'truly unmutated' IGHV genes. Although the clinical implications of this observation remain to be defined, our findings offer a new perspective into the immunobiology of CLL, alluding to the operation of VH CDR3-restricted SHM in U-CLL.
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Immunoglobulin heavy chain
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The somatic hypermutation (SHM) status of the clonotypic, rearranged immunoglobulin heavy variable (IGHV) gene is an established prognostic and predictive marker in chronic lymphocytic leukemia (CLL). Analysis of SHM is generally performed by polymerase chain reaction (PCR)-amplification of clonal IGHV-IGHD-IGHJ gene rearrangements followed by sequencing to identify IGHV gene sequences and germline identity. Targeted-hybridization next-generation sequencing (NGS) can simultaneously assess clonality and other genetic aberrations. However, it has limitations for SHM analysis due to sequence similarity between different IGHV genes and mutations introduced by SHM, which can affect alignment efficiency and accuracy. We developed a novel SHM assessment strategy using a targeted-hybridization NGS approach (EuroClonality- NDC assay) and applied it to 331 samples of lymphoproliferative disorder (LPD). Our strategy focuses on analyzing the sequence downstream to the clonotypic, rearranged IGHJ gene up to the IGHM enhancer (IGHJ-E) which provides more accurate alignment. Overall, 84/95 (88.4%) CLL cases with conventional SHM data showed concordant SHM status, increasing to 91.6% when excluding borderline cases. Additionally, IGHJ-E mutation analysis in a wide range of pre- and post-germinal center LPD showed significant correlation with differentiation and lineage status, suggesting that IGHJ-E analysis is a promising surrogate marker enabling SHM to be reported using NGS-capture strategies and whole genome sequencing.
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IGHD
Immunoglobulin heavy chain
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Abstract Background Somatic hypermutation (SHM) status of the immunoglobulin heavy variable (IGHV) gene plays a crucial role in determining the prognosis and treatment of patients with chronic lymphocytic leukemia (CLL). A common approach for determining SHM status is multiplex polymerase chain reaction and Sanger sequencing of the immunoglobin heavy locus; however, this technique is low throughput, is vulnerable to failure, and does not allow multiplexing with other diagnostic assays. Methods Here we designed and validated a DNA targeted capture approach to detect immunoglobulin heavy variable somatic hypermutation (IGHV SHM) status as a submodule of a larger next-generation sequencing (NGS) panel that also includes probes for ATM, BIRC3, CHD2, KLHL6, MYD88, NOTCH1, NOTCH2, POT1, SF3B1, TP53, and XPO1. The assay takes as input FASTQ files and outputs a report containing IGHV SHM status and V allele usage following European Research Initiative on CLL guidelines. Results We validated the approach on 35 CLL patient samples, 34 of which were characterized using Sanger sequencing. The NGS panel identified the IGHV SHM status of 34 of 35 CLL patients. We showed 100% sensitivity and specificity among the 33 CLL samples with both NGS and Sanger sequencing calls. Furthermore, we demonstrated that this panel can be combined with additional targeted capture panels to detect prognostically important CLL single nucleotide variants, insertions/deletions, and copy number variants (TP53 copy number loss). Conclusions A targeted capture approach to IGHV SHM detection can be integrated into broader sequencing panels, allowing broad CLL prognostication in a single molecular assay.
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Background: The mutational status of the variable region of the Immunoglobulin heavy-chain (IGHV) gene is one of the most robust prognostic markers in Chronic Lymphocytic Leukemia (CLL), allowing the identification of 2 groups with different clinical behavior. Those with no or few somatic mutations (unmutated CLL, UM-CLL) with a more aggressive course of their disease, and those with a heavier load of mutations (mutated, M-CLL), with a more indolent disease. European Research Initiative on CLL (ERIC) has defined clear guidelines for Immunoglobulin gene sequence analysis. Materials and Methods: Patients with CLL in our institution were studied for productive IGHV rearrangements and its mutational status. There were no exclusion criteria for the analysis of this prognostic marker. IGHV-D-J gene rearrangements and mutational status were analyzed between 6/2016 and 2/2019. Nucleic acid used was genomic DNA (gDNA) and ERIC guidelines were followed. High molecular weight DNA was isolated from all patients and amplified using forward Leader primers combined with JH reverse consensus primer. In those cases, in which leader primers were unsuccessful at providing a product that could be sequenced, VH FR1 primers were used. Direct bidirectional sequencing was performed and Stereotype B cell receptors were analyzed. Results: From 150 samples received and analyzed, 138 productive IGHV-IGHD-IGHJ rearrangements were identified, 12 patients had insufficient leukemic cells for the analysis. Of 138 patients 54 (39%) were UM-CLL and 84 (61%) were M-CLL. Within this last group, 12 were considered “borderline” M-CLL. The most frequent IGHV family in this series was IGHV3, followed by IGHV4 and IGHV1. Double rearrangements were detected in 16 of the cases. Stereotype B cell receptors were found in 16 patients. Conclusion: These results show a slightly higher incidence on M-CLL than the published data. We believe this is due to a high proportion of asymptomatic patients with no need of treatment, in this cohort. The most frequent used IGHV family was IGHV-3 while IGHV4 and IGHV1 were in second and third place, respectively. The frequency of Stereotyped BcRs was lower from those observed in western countries cohorts. These results support previous published experience in other Latin American countries. Longer follow up will be necessary to determine the impact of this molecular factor in the clinical behavior of this group of patients. Keywords: gene rearrangement; immunoglobulins (Ig).
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Immunoglobulin heavy chain
IGHD
genomic DNA
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IGHD
Immunoglobulin gene
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H νεοπλασματική εκτροπή είναι το αποτέλεσμα της διαταραχής των ρυθμιστικών μηχανισμών που διέπουν τον κυτταρικό πολλαπλασιασμό και την απόπτωση.Μεταξύ των κακοηθειών του αιμοποιητικού ιστού, η χρόνια λεμφοκυτταρική λευχαιμία (ΧΛΛ) θεωρείται νόσος-υπόδειγμα για τη μελέτη του ρόλου των διαταραχών του κυτταρικού κύκλου και της απόπτωσης στη νεοπλασματική εκτροπή και χαρακτηρίζεται από μεγάλη κλινική ετερογένεια παρά τον ομοιογενή κλινικό και εργαστηριακό φαινότυπο των ασθενών κατά τη διάγνωση. Πολλά δεδομένα υποδεικνύουν πως το μικροπεριβάλλον διαδραματίζει καθοριστικό ρόλο στην ανάπτυξη και εξέλιξη της ΧΛΛ. Κεντρικό ρόλο στη λευχαιμογένεση διαδραματίζει ο Β κυτταρικός υποδοχέας (B cell receptor, BcR). ΟBcR ρυθμίζει όλες σχεδόν τις λειτουργίες των φυσιολογικών Β λεμφοκυττάρων, συναρμολογείται από την επιφανειακή ανοσοσφαιρίνη IgΗ και τις διαμεμβρανικές πρωτεΐνες Igα (CD79a) και Igβ (CD79b). Η επιφανειακή ανοσοσφαιρίνη κωδικοποιείται αρχικά από τα γονίδια IGHV, IGHD και IGHJ της μεταβλητής περιοχής των βαριών αλυσίδων που αναδιατάσσονται με ιεραρχικό τρόπο κατά την ωρίμανση των Β λεμφοκυττάρων. Η αναδιάταξη των ανασυνδυασμένων γονιδίωνIGHV-IGHD-IGHJ με τη σταθερή περιοχή τη ΙGHM ακολουθείται από την αναδιάταξη των ελαφριών αλυσίδων και καταλήγει στην έκφραση της ανοσοσφαιρίνης IgM στην επιφάνεια των Β λεμφοκυττάρων. Η αναγνώριση και η πρόσδεση του αντιγόνου στη μεταβλητή περιοχή της ανοσοσφαιρίνης ενεργοποιεί τα Β λεμφοκύτταρα που διαφοροποιούνται στα βλαστικά κέντρα μέσω της σωματικής υπερμεταλλαξιγένεσης (ΣΥΜ). Το τελικό αποτέλεσμα της ΣΥΜ είναι η εισαγωγή μεταλλάξεων στην μεταβλητή περιοχή των ανοσοσφαιρινών και η δημιουργία ανοσοσφαιρινών με υψηλότερη συγγένεια για το αντιγόνο.Η αντιγονική διέγερση μέσω του BcR διαδραματίζει σημαντικό ρόλο στην ανάπτυξη και εξέλιξη της ΧΛΛ. Τo φορτίο των σωματικών μεταλλάξεων των γονιδίων IGHVαποτελεί σήμερα τον πιο σημαντικό προγνωστικό παράγοντα στους ασθενείς με ΧΛΛ. Tο ποσοστό νουκλεοτιδικής ταυτότητας 98% του αναδιαταγμένου γονιδίουIGHV του νεοπλασματικού κλώνου με το αντίστοιχο μη αναδιαταγμένο γονίδιο IGHV χρησιμοποιείται ευρέως για την κατάταξη των αναδιατάξεων στη ΧΛΛ σε μεταλλαγμένες και αμετάλλακτες. To όριο ομολογίας 98% αν και δεν έχει βιολογική σημασία, επιλέχθηκε αρχικά ώστε ν’ αποφευχθεί το ενδεχόμενο κάποιες από τις διαφορές ν’ αντιστοιχούν σε άγνωστους πολυμορφισμούς του γενετικού τόπου IGH.Πρόσφατες μελέτες έδειξαν ότι η αλληλεπίδραση των νεοπλασματικών λεμφοκυττάρων με το μικροπεριβάλλον μέσω του Β κυτταρικού υποδοχέα (BcR)αλλά και των υποδοχέων της έμφυτης ανοσίας (TLRs) παίζει σημαντικό ρόλο στη νεοπλασματική εκτροπή. Η συνεργασία προσαρμοστικής και έμφυτης ανοσίας αποτελεί ιδιότητα των φυσιολογικών αλλά και των αυτοαντιδραστικών λεμφοκυττάρων. Τα δεδομένα από τη συνδιέγερση BcR/TLR στη ΧΛΛ είναι πολύ περιορισμένα επειδή οι περισσότερες μελέτες αφορούν μεμονωμένη in vitroδιέγερση είτε του BcR είτε των TLRs.Στην παρούσα διδακτορική διατριβή μελετήθηκαν: (i) τα ιδιαίτερα μοριακά χαρακτηριστικά του BcR στη ΧΛΛ και διερευνήθηκε πιθανή συσχέτισή τους με την κλινική επιθετικότητα της νόσου, και (ii) ο αντίκτυπος της in vitro διέγερσης του BcR,των TLR7 και TLR9 μεμονωμένα ή σε συνδυασμό (BcR/TLR7 και BcR/TLR9) στην επιβίωση και την απόπτωση των νεοπλασματικών κυττάρων της ΧΛΛ. Αρχικά αναλύθηκαν οι κλωνικές αναδιατάξεις των γονιδίων IGHV-IGHD-IGHJ σε 799 ασθενείς με ΧΛΛ. Μελετήθηκε το ρεπερτόριο και το φορτίο των μεταλλάξεων των γονιδίων IGH, καθώς και τα μοριακά χαρακτηριστικά των μεταλλάξεων. Οι αναδιατάξεις IGHV-IGHD-IGHJ αρχικά διακρίθηκαν σε αμετάλλακτες (Α) και μεταλλαγμένες (Μ) με βάση το γενικά αποδεκτό όριο ομολογίας 98% του γονιδίουIGHV σε σχέση με το αντίστοιχο μη αναδιαταγμένο γονίδιο ΙGHV. Στη συνέχεια, οι αναδιατάξεις διακρίθηκαν περαιτέρω σε διαδοχικά υποσύνολα που διέφεραν μεταξύ τους κατά 1% ως προς την νουκλεοτιδική ταυτότητά τους με το αντίστοιχομη αναδιαταγμένο γονίδιο IGHV και διερευνήθηκε η πιθανή προγνωστική αξία αυτών των υποσυνόλων στο χρόνο έναρξης θεραπείας και την ολική επιβίωση των ασθενών. Τα αποτελέσματα της παρούσας μελέτης επιβεβαίωσαν προηγούμενες μελέτες αναφορικά με την επιλεκτικότητα του ρεπερτορίου και έδειξαν ότι η εισαγωγή των μεταλλάξεων σε όλες τις υποομάδες με ομολογία <100%πραγματοποιήθηκε στα πλαίσια του κλασσικού μηχανισμού σωματικής υπερμεταλλαξιγένεσης. Επιπλέον, έδειξαν ότι το όριο 98% υπερτερεί ως προς την προγνωστική σημασία για τους ασθενείς με ΧΛΛ. Στη συνέχεια μελετήθηκαν τα αποτελέσματα της in vitro διέγερσης των BcR, TLR7και TLR9 με αντι-IgM, Imiquimod και CpG, αντιστοίχως, μεμονωμένα ή σε συνδυασμό, σε 21 ασθενείς με ΧΛΛ (11 Μ-ΧΛΛ, 10 Α-ΧΛΛ). Τα αποτελέσματα της διέγερσης εκτιμήθηκαν με προσδιορισμό της pERK, ενώ η επαγωγή της απόπτωσης με προσδιορισμό της κασπάσης 8 και της PARP. Αυξημένα επίπεδα pΕRΚ παρατηρήθηκαν μετά από μεμονωμένη διέγερση των BcR, TLR7 και TLR9 στην ΑΧΛΛ,ενώ στη Μ-ΧΛΛ μόνο με συνδιέγερση BcR/TLR. Αντίθετα, η μεμονωμένη διέγερση των TLR7 και TLR9 αλλά και η συνδιέγερση BcR/TLR βρέθηκαν να προκαλούν επαγωγή της απόπτωσης κυρίως στη M-ΧΛΛ. Η διαφορετική ανταπόκριση των νεοπλασματικών λεμφοκυττάρων στη Μ-ΧΛΛ έναντι της Α-ΧΛΛ πιθανότατα υποδεικνύει διαφορετικό λειτουργικό αποτέλεσμα, που αντικατοπτρίζεται τελικά στη συμπεριφορά του λευχαιμικού κλώνου και τροποποιεί το ρυθμό κυτταρικού πολλαπλασιασμού και την απόπτωση.
IGHV@
TLR9
breakpoint cluster region
IGHD
TLR7
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Survival of patients with B cell chronic lymphocytic leukemia (B-CLL) can be predicted by analysis of mutations in the immunoglobulin heavy chain variable gene (IGHV). Patients without mutations (unmutated [UM]) are at greater risk for disease progression and death than patients with mutations (M). Despite this broad prognostic difference, there remains wide intragroup variation in the clinical outcome of UM patients, especially those with low/intermediate Rai risk disease. We evaluated UM B-CLL patients with low/intermediate Rai risk to determine the relationship between IGHV, IGH diversity (IGHD), and IGH joining (IGHJ) gene usage and time to treatment (TTT). Irrespective of IGHV usage, UM patients whose B-CLL cells expressed the IGHD3-3 gene had a significantly shorter TTT than other UM B-CLL patients, and specifically, use of the IGHD3-3 gene in reading frame 2 (RF2) predicted shorter TTT. As expected, Rai risk was the best single prognostic factor for TTT; however, IGHD usage was also a significant variable for TTT. Therefore, both IGHD gene and IGHD RF usage have prognostic relevance in UM B-CLL patients with low/intermediate Rai risk disease. In addition, these data support the concept that antigen-driven selection of specific Ig receptors plays a role in the clinical course of B-CLL.
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IGHD
Immunoglobulin D
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