Antigen receptor gene rearrangements reflect on the heterogeneity of adult Acute Lymphoblastic Leukaemia (ALL) with implications of cell-origin of ALL subgroups – a UKALLXII study
Anouska Casanova
Haematology Department, Royal Free Hospital, London
Search for more papers by this authorAnthony V. Moorman
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne
Search for more papers by this authorSue Richards
CTSU, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford
Search for more papers by this authorGeorgina Buck
CTSU, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford
Search for more papers by this authorAnthony H. Goldstone
University College London Hospital, London, UK
Search for more papers by this authorAdele K. Fielding
Haematology Department, Royal Free Hospital, London
Search for more papers by this authorLetizia Foroni
Haematology Department, Royal Free Hospital, London
Present address: L. Foroni, Haematology Department; Hammersmith Campus, Imperial College, Du Cane Road, London W12 0NN, UK.
Search for more papers by this authorAnouska Casanova
Haematology Department, Royal Free Hospital, London
Search for more papers by this authorAnthony V. Moorman
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne
Search for more papers by this authorSue Richards
CTSU, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford
Search for more papers by this authorGeorgina Buck
CTSU, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford
Search for more papers by this authorAnthony H. Goldstone
University College London Hospital, London, UK
Search for more papers by this authorAdele K. Fielding
Haematology Department, Royal Free Hospital, London
Search for more papers by this authorLetizia Foroni
Haematology Department, Royal Free Hospital, London
Present address: L. Foroni, Haematology Department; Hammersmith Campus, Imperial College, Du Cane Road, London W12 0NN, UK.
Search for more papers by this authorSummary
Cytogenetic and molecular investigations of Acute Lymphoblastic Leukaemia (ALL) have identified the existence of distinct clinical subgroups. Molecular monitoring of clonal Immunoglobulin and T cell receptor (IG/TR) gene rearrangements has become an important tool in stratification of therapy of ALL. In order to determine whether certain features of the patient-specific rearrangements could hold further prognostic clues or provide information on the cell of origin of ALL, a comprehensive analysis of structural and biological features (V gene usage, coding frame and mutational status and complementarity-determining region -III length) of 473 IG/TR rearrangements identified in 229 adults with ALL was carried out. Distinct variable-gene usage profiles were identified between ALL subgroups, particularly for patients positive for BCR-ABL1 compared to MLL-AFF1 positive leukaemias; suggesting that the former is derived from a more mature B progenitor. Interestingly, occurrence of TRGV1-TRGV8 was prognostic for better event-free survival (31% at 4 years with vs. 0% at 4 years without, P = 0·05). The heterogeneity in clinical outcome is suggested by the basic molecular processes of antigen receptor gene rearrangements as shown in this work.
References
- Brezinschek, H.P., Brezinschek, R.I. & Lipsky, P.E. (1995) Analysis of the heavy chain repertoire of human peripheral B cells using single-cell polymerase chain reaction. Journal of immunology, 155, 190–202.
- Bruggemann, M., Raff, T., Flohr, T., Gokbuget, N., Nakao, M., Droese, J., Luschen, S., Pott, C., Ritgen, M., Scheuring, U., Horst, H.A., Thiel, E., Hoelzer, D., Bartram, C.R. & Kneba, M. (2006) Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood, 107, 1116–1123.
- Castor, A., Nilsson, L., Strand-Grundstrom, I., Buitenhuis, M., Ramirez, C., Anderson, K., Strombeck, B., Garwicz, S., Bekassy, A.N., Schmiegelow, K., Lausen, B., Hokland, P., Lehmann, S., Juliusson, G., Johansson, B. & Jacobsen, S.E. (2005) Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nature medicine, 11, 630–637.
- Chiaretti, S., Li, X., Gentleman, R., Vitale, A., Wang, K.S., Mandelli, F., Foa, R. & Ritz, J. (2005) Gene Expression Profiles of B-lineage Adult Acute Lymphocytic Leukemia Reveal Genetic Patterns that Identify Lineage Derivation and Distinct Mechanisms of Transformation. Clinical Cancer Research, 11, 7209–7219.
- Chim, J.C., Coyle, L.A., Yaxley, J.C., Cole-Sinclair, M.F., Cannell, P.K., Hoffbrand, V.A. & Foroni, L. (1996) The use of IgH fingerprinting and ASO-dependent PCR for the investigation of residual disease (MRD) in ALL. British Journal of Haematology, 92, 104–115.
- Cobaleda, C., Gutierrez-Cianca, N., Perez-Losada, J., Flores, T., Garcia-Sanz, R., Gonzalez, M. & Sanchez-Garcia, I. (2000) A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. Blood, 95, 1007–1013.
- Cox, C.V., Evely, R.S., Oakhill, A., Pamphilon, D.H., Goulden, N.J. & Blair, A. (2004) Characterization of acute lymphoblastic leukemia progenitor cells. Blood, 104, 2919–2925.
- Coyle, L.A., Papaioannou, M., Yaxley, J.C., Chim, J.S., Attard, M., Hoffbrand, A.V. & Foroni, L. (1996) Molecular analysis of the leukaemic B cell in adult and childhood acute lymphoblastic leukaemia. British Journal of Haematology, 94, 685–693.
- Duke, V.M., Gandini, D., Sherrington, P.D., Lin, K., Heelan, B., Amlot, P., Mehta, A.B., Hoffbrand, A.V. & Foroni, L. (2003) V(H) gene usage differs in germline and mutated B-cell chronic lymphocytic leukemia. Haematologica, 88, 1259–1271.
- Dupret, C., Asnafi, V., Leboeuf, D., Millien, C., Ben, A.R., Preudhomme, C., Beldjord, K., Delabesse, E. & Macintyre, E. (2005) IgH/TCR rearrangements are common in MLL translocated adult AML and suggest an early T/myeloid or B/myeloid maturation arrest, which correlates with the MLL partner. Leukemia, 19, 2337–2338.
- Van Es, J.H., Raaphorst, F.M., Van Tol, M.J., Meyling, F.H. & Logtenberg, T. (1993) Expression pattern of the most JH-proximal human VH gene segment (VH6) in the B cell and antibody repertoire suggests a role of VH6-encoded IgM antibodies in early ontogeny. Journal of immunology, 150, 161–168.
- Foroni, L. & Hoffbrand, A.V. (2002) Molecular analysis of minimal residual disease in adult acute lymphoblastic leukaemia. Best Practice & Research. Clinical Haematology, 15, 71–90.
- Gameiro, P., Mortuza, F.Y., Hoffbrand, A.V. & Foroni, L. (2002) Minimal residual disease monitoring in adult T-cell acute lymphoblastic leukemia: a molecular based approach using T-cell receptor G and D gene rearrangements. Haematologica, 87, 1126–1134.
- Hamblin, T.J., Davis, Z., Gardiner, A., Oscier, D.G. & Stevenson, F.K. (1999) Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood, 94, 1848–1854.
- Harris, N.L., Jaffe, E.S., Diebold, J., Flandrin, G., Muller-Hermelink, H.K., Vardiman, J., Lister, T.A. & Bloomfield, C.D. (2000) The World Health Organization classification of neoplastic diseases of the haematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Histopathology, 36, 69–86.
- Jansen, M.W., Corral, L., Van Der Vellden, V., Panzer-Grumayer, R., Schrappe, M., Schrauder, A., Marschalek, R., Meyer, C., Den Boer, M.L., Hop, W.J., Valsecchi, M.G., Basso, G., Biondi, A., Pieters, R. & Van Dongen, J.J. (2007) Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement. Leukemia, 21, 633–641.
- Kohlmann, A., Schoch, C., Schnittger, S., Dugas, M., Hiddemann, W., Kern, W. & Haferlach, T. (2004) Pediatric acute lymphoblastic leukemia (ALL) gene expression signatures classify an independent cohort of adult ALL patients. Leukemia, 18, 63–71.
- Kong, Y., Yoshida, S., Saito, Y., Doi, T., Nagatoshi, Y., Fukata, M., Saito, N., Yang, S.M., Iwamoto, C., Okamura, J., Liu, K.Y., Huang, X.J., Lu, D.P., Shultz, L.D., Harada, M. & Ishikawa, F. (2008) CD34+CD38+CD19+ as well as CD34+CD38-CD19+ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL. Leukemia, 22, 1207–1213.
- Lampert, F., Harbott, J., Ludwig, W.D., Bartram, C.R., Ritter, J., Gerein, V., Neidhardt, M., Mertens, R., Graf, N. & Riehm, H. (1987) Acute leukemia with chromosome translocation (4;11): 7 new patients and analysis of 71 cases. Blut, 54, 325–335.
- Langerak, A.W., Szczepanski, T., Van Der, B.M., Wolvers-Tettero, I.L. & Van Dongen, J.J. (1997) Heteroduplex PCR analysis of rearranged T cell receptor genes for clonality assessment in suspect T cell proliferations. Leukemia, 11, 2192–2199.
- Li, A., Rue, M., Zhou, J., Wang, H., Goldwasser, M.A., Neuberg, D., Dalton, V., Zuckerman, D., Lyons, C., Silverman, L.B., Sallan, S.E. & Gribben, J.G. (2004) Utilization of Ig heavy chain variable, diversity, and joining gene segments in children with B-lineage acute lymphoblastic leukemia: implications for the mechanisms of VDJ recombination and for pathogenesis. Blood, 103, 4602–4609.
- Meffre, E., Milili, M., Blanco-Betancourt, C., Antunes, H., Nussenzweig, M.C. & Schiff, C. (2001) Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development. The Journal of Clinical Investigation, 108, 879–886.
- Messmer, D., Telusma, G., Wasil, T., Messmer, B.T., Allen, S., Rai, K.R. & Chiorazzi, N. (2004) Dendritic cells from chronic lymphocytic leukemia patients are normal regardless of Ig V gene mutation status. Molecular Medicine, 10, 96–103.
- Moorman, A.V., Harrison, C.J., Buck, G.A., Richards, S.M., Secker-Walker, L.M., Martineau, M., Vance, G.H., Cherry, A.M., Higgins, R.R., Fielding, A.K., Foroni, L., Paietta, E., Tallman, M.S., Litzow, M.R., Wiernik, P.H., Rowe, J.M., Goldstone, A.H. & Dewald, G.W. (2007) Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood, 109, 3189–3197.
- Mortuza, F.Y., Moreira, I.M., Papaioannou, M., Gameiro, P., Coyle, L.A., Gricks, C.S., Amlot, P., Prentice, H.G., Madrigal, A., Hoffbrand, A.V. & Foroni, L. (2001) Immunoglobulin heavy-chain gene rearrangement in adult acute lymphoblastic leukemia reveals preferential usage of J(H)-proximal variable gene segments. Blood, 97, 2716–2726.
- Oscier, D.G., Gardiner, A.C., Mould, S.J., Glide, S., Davis, Z.A., Ibbotson, R.E., Corcoran, M.M., Chapman, R.M., Thomas, P.W., Copplestone, J.A., Orchard, J.A. & Hamblin, T.J. (2002) Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood, 100, 1177–1184.
- Raaphorst, F.M., Raman, C.S., Tami, J., Fischbach, M. & Sanz, I. (1997) Human Ig heavy chain CDR3 regions in adult bone marrow pre-B cells display an adult phenotype of diversity: evidence for structural selection of DH amino acid sequences. International Immunology, 9, 1503–1515.
- Szczepanski, T. (2007) Why and how to quantify minimal residual disease in acute lymphoblastic leukemia? Leukemia, 21, 622–626.
- Thorselius, M., Krober, A., Murray, F., Thunberg, U., Tobin, G., Buhler, A., Kienle, D., Albesiano, E., Maffei, R., Dao-Ung, L.P., Wiley, J., Vilpo, J., Laurell, A., Merup, M., Roos, G., Karlsson, K., Chiorazzi, N., Marasca, R., Dohner, H., Stilgenbauer, S. & Rosenquist, R. (2006) Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status. Blood, 107, 2889–2894.
- Tobin, G., Soderberg, O., Thunberg, U. & Rosenquist, R. (2004) V(H)3-21 gene usage in chronic lymphocytic leukemia--characterization of a new subgroup with distinct molecular features and poor survival. Leukemia & Lymphoma, 45, 221–228.
- Widhopf, G.F. & Kipps, T.J. (2001) Normal B cells express 51p1-encoded Ig heavy chains that are distinct from those expressed by chronic lymphocytic leukemia B cells. Journal of immunology, 166, 95–102.
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