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Immunogenetica della LLC: implicazionui patogenetiche e prognostiche mediante analisi del gene IGHV1-69

Orvieto, Palazzo Coelli 21 Novembre 2009. Immunogenetica della LLC: implicazionui patogenetiche e prognostiche mediante analisi del gene IGHV1-69. Francesco Forconi Ematologia e Trapianti Università di Siena. IGH Variable region. IGHV-D-J rearrangement. Hypervariable Region. HCDR3. HCDR1.

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Immunogenetica della LLC: implicazionui patogenetiche e prognostiche mediante analisi del gene IGHV1-69

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  1. Orvieto, Palazzo Coelli 21 Novembre 2009 Immunogenetica della LLC: implicazionui patogenetiche e prognostiche mediante analisi del gene IGHV1-69 Francesco Forconi Ematologia e Trapianti Università di Siena

  2. IGH Variable region IGHV-D-J rearrangement Hypervariable Region HCDR3 HCDR1 HCDR2 HFR1 HFR2 HFR3 N Region IGHV IGHD IGHJ 51 IGHV genes 27 IGHD genes 6 IGHJ genes

  3. Antigen Midollo Osseo Organilinfoidisecondari/ Marginal Zone IgD IgM IgG UM-CLL 40 % M-CLL 60% MUTAZIONI SOMATICHE IgM IgM Ig IgD Ig Cellula B immatura Cellula B naive Cellula B memoria

  4. Sopravvivenza e stato mutazionale dei geni IGHV 17 anni 293 mesi 9 anni 95 mesi Damle, R. N. et al. Blood 1999;94:1840-1847 Hamblin, T. J. et al. Blood 1999;94:1848-1854

  5. Antigen BCR IgD IgM IgG UM-CLL 40 % M-CLL 60% ZAP70 + ZAP70 - • phosphorylation of p72Syk • intracellular [Ca(2+)](i) • Rapid disease progression • Slow disease progression

  6. Shared sequence “stereotypic” characteristics of the HCDR3 suggest antigen selection of the leukemic clones

  7. Top 10 in CLL Murray et al BLOOD, 2008 (111).

  8. Selective stimulation of the B cell of origin (?) • Antigenic drive continuing following transformation (?) • Are Stereotypes CLL-specific?

  9. IGHV1-69 N=214 • 14 alleli di cui i più frequenti IGHV1-69*01, *02, e *12 (riconosciuti dall’anticorpo anti-51p1 G6) • Infrequente nella popolazione B del sangue periferico da analisi molecolari (Lipsky: <1%) • 13% di tutte le CLL • 30% delle UM-CLL • 227/259 (88%) cases >98% homology to germline alleles • Dal 47% al 55% delle CLL stereotipate • Nella CLL mediana dei casi 1-69 è 69 anni

  10. 51p1-IGHJ6 rearrangements expressed in the normal B cell repertoire

  11. Comparison of the HCDR3 sequences of CLL and normal B cells in the 51p1-IGHJ6-derived subset 5.

  12. G6-positive (IGHV1-69 51p1-expressing) B- cells are part of the conventional resting naïve B-cell population. • 4.8% of all B-cells. • CD27-negative, indicative of naïve B cells. • IgM+ IgD+ CD23+ CD5- CD38+ (as in G6-ve naïve B-cells). • A small percentage of CD5+ B cells, not found in the memory B-cell subset. • CD38 expression was similarly high in naïve and G6-positive populations. • IgK (65%) : IgL (35%) comparable to normal B cells and 51p1+ve CLL (data not shown). • Absence of activation markers (CD25 and CD69).

  13. Are Stereotypes CLL-specific? • by focusing only on the IGHV1-69-derived sequences combined to IGHJ6 in age-matched normal subjects, we have found “Stereotypic” sequences of several of the major subsets described in CLL and of new potential subsets in > 33% sequences cloned from normal donors. • it is possible that this conserved sequences are a likely source of transformation to U-CLL and that they derive from the naïve B-cell repertoire. • Little similarity in the HCDR3 junctional amino acids between cases of CLL and little similarity within normal B cells

  14. How does antigenic stimulation would continue following transformation? HCDR3 driven clustering to identify prognostic subsets Stamatopoulos, K. et al. Blood 2007;109:259-270

  15. CRO AVIANO Subset 1

  16. IGHV4-39 and transformation to Richter Sydrome p<.001 No IGHV4-39 IGHV4-39 IGHV4-39/stereotypic HCDR3 IGHV4-39/no stereotypic HCDR3 No IGHV4-39/stereotypic HCDR3 No IGHV4-39/no stereotypic HCDR3 Rossi, Clinical Cancer Research 2009

  17. IGHV1-69 & progression Stamatopoulos, K. et al. Blood 2007;109:259-270

  18. HCDR3 length in CLL HCDR3 length in 1-69

  19. Summary • By investigating the IGHV1-69-J6 repertoire we can observe that “CLL-specific” HCDR3 are present in the normal individuals • The subsets with different clinical behavior may rely on (super)antigen stimulation. However, it remains to be demonstrated that stimulation occurs through specific CDR3 interaction. • Lack of different behavior (CLL progression and overall survival) between stereotyped and non stereotyped UM-CLL using IGHV1-69 point to antigen stimulation via CDR3-independent antigen. • Clinically, mutational status keeps being confirmed as the relevant tool to stratify progression risk in CLL

  20. p66Shc levels and clinical behavior of U-CLL and M-CLL Capitani et al, submitted 2009

  21. Siena EmanueleCencini Elisa Sozzi Nagaja Capitani CosimaBaldari Novara Davide Rossi Gianluca Gaidano Aviano Riccardo Bomben Valter Gattei Bellinzona Andrea Rinaldi Francesco Bertoni Niguarda Milano Silvio Veronese Marco Montillo Roma DimitarEfremov Luca Laurenti Giovanni Del Poeta Modena Roberto Marasca Torino Marta Coscia Massimo Massaia Southampton Kathy Potter Freda K. Stevenson Salonicco KostasStamatopoulos

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