The outcome of molecular-cytogenetic subgroups in pediatric T-cell acute lymphoblastic leukemia: a retrospective study of patients treated according to DCOG or COALL protocols.

BACKGROUND AND OBJECTIVES Subgroups of T-cell acute lymphoblastic leukemia (T-ALL), defined according to recurrent cytogenetic aberrations, may have different prognoses. The aim of this study was to determine the prognostic relevance of molecular-cytogenetic abnormalities in pediatric patients using quantitative real-time polymerase chain reaction and fluorescence in situ hybridization. DESIGN AND METHODS The patients were assigned to TAL1, HOX11/TLX1, HOX11L2/TLX3, or CALM-AF10 subgroups. The cytogenetic subgroups were characterized in relation to immunophenotype and the expression of aberrantly expressed transcription factors. RESULTS In our cohort study, CALM-AF10 was associated with an immature immunophenotype and poor outcome (p=0.005). HOX11L2 was associated with both immunophenotypically immature cases as well as cases committed to the gammadelta-lineage. HOX11L2 was significantly associated with poor outcome (p=0.01), independently of the expression of CD1 or the presence of NOTCH1 mutations. TAL1 abnormalities were associated with alphabeta-lineage commitment, and tended to be associated with a good outcome. Cells in HOX11 cases resembled early CD1-positive cortical thymocytes without expression of Cytbeta and TCR molecules. In relation to the expression of early T-cell transcription factors, high TAL1 levels were found in immunophenotypically-advanced cases, whereas high LYL1 levels were found in immature subgroups. INTERPRETATION AND CONCLUSIONS The reported outcomes for HOX11L2-rearranged T-ALL cases are conflicting; the prognostic impact may depend on the therapy given. In our cohort, this cytogenetic aberration was associated with a poor outcome. Our data on CALM-AF10 rearranged T-ALL, albeit based on only three patients, suggest that this type of leukemia is associated with a poor outcome.

[1]  F. Speleman,et al.  Molecular cytogenetic study of 126 unselected T-ALL cases reveals high incidence of TCRβ locus rearrangements and putative new T-cell oncogenes , 2006, Leukemia.

[2]  K. Wenner,et al.  Serum asparaginase activities and asparagine concentrations in the cerebrospinal fluid after a single infusion of 2,500 IU/m2 PEG asparaginase in children with ALL treated according to protocol COALL‐06‐97 , 2006, Pediatric blood & cancer.

[3]  S. Armstrong,et al.  Molecular genetics of acute lymphoblastic leukemia. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  H. Sather,et al.  Significance of HOX11L2/TLX3 expression in children with T-cell acute lymphoblastic leukemia treated on Children's Cancer Group protocols , 2005, Leukemia.

[5]  P. Marynen,et al.  NUP214-ABL1 amplification in t(5;14)/HOX11L2-positive ALL present with several forms and may have a prognostic significance , 2005, Leukemia.

[6]  E. Macintyre,et al.  Age-related phenotypic and oncogenic differences in T-cell acute lymphoblastic leukemias may reflect thymic atrophy. , 2004, Blood.

[7]  A. Ferrando,et al.  Various types of rearrangements target TLX3 locus in T‐cell acute lymphoblastic leukemia , 2004, Genes, chromosomes & cancer.

[8]  Andrew P. Weng,et al.  Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia , 2004, Science.

[9]  J. O'neil,et al.  TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB. , 2004, Cancer cell.

[10]  M. Caligiuri,et al.  Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia , 2004, The Lancet.

[11]  W. Kern,et al.  Satelite Symposium V, Meet-the-Professor Sessions I and II, Main Sessions I-IX , 2004, Annals of Hematology.

[12]  F. Speleman,et al.  Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. , 2004, Blood.

[13]  H. Cavé,et al.  Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – A Europe Against Cancer Program , 2003, Leukemia.

[14]  F. Speleman,et al.  t(5;14)/HOX11L2-positive T-cell acute lymphoblastic leukemia. A collaborative study of the Groupe Français de Cytogénétique Hématologique (GFCH) , 2003, Leukemia.

[15]  E. Macintyre,et al.  CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCRγδ lineage , 2003 .

[16]  N. Heerema,et al.  Expression of HOX11 in childhood T-lineage acute lymphoblastic leukaemia can occur in the absence of cytogenetic aberration at 10q24: a study from the Children's Cancer Group (CCG) , 2003, Leukemia.

[17]  E. Macintyre,et al.  Analysis of TCR, pT alpha, and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment. , 2003, Blood.

[18]  S. Armstrong,et al.  Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia. , 2003, Blood.

[19]  P. Lutz,et al.  High incidence of Hox11L2 expression in children with T-ALL , 2002, Leukemia.

[20]  J. Whitlock,et al.  Disruption of the RanBP17/Hox11L2 region by recombination with the TCRδ locus in acute lymphoblastic leukemias with t(5;14)(q34;q11) , 2002, Leukemia.

[21]  T. Lister,et al.  Molecular characterization of a new recombination of the SIL/TAL‐1 locus in a child with T‐cell acute lymphoblastic leukaemia , 2002, British journal of haematology.

[22]  J. Zucman‐Rossi,et al.  HOX11L2 expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis. , 2002, Blood.

[23]  B. Dörken,et al.  In vitro susceptibility to dexamethasone- and doxorubicin-induced apoptotic cell death in context of maturation stage, responsiveness to interleukin 7, and early cytoreduction in vivo in childhood T-cell acute lymphoblastic leukemia. , 2002, Blood.

[24]  E. Lander,et al.  Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. , 2002, Cancer cell.

[25]  R. Heilig,et al.  A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia , 2001, Leukemia.

[26]  J. Raemaekers,et al.  A novel method to compensate for different amplification efficiencies between patient DNA samples in quantitative real-time PCR. , 2001, The Journal of molecular diagnostics : JMD.

[27]  J. Shuster,et al.  New recurring cytogenetic abnormalities and association of blast cell karyotypes with prognosis in childhood T-cell acute lymphoblastic leukemia: a pediatric oncology group report of 343 cases. , 2000, Blood.

[28]  T. Hoang,et al.  SCL and LMO1 alter thymocyte differentiation: inhibition of E2A-HEB function and pre-Tα chain expression , 2000, Nature Immunology.

[29]  A. Look,et al.  Significance of commonly used prognostic factors differs for children with T cell acute lymphocytic leukemia (ALL), as compared to those with B-precursor ALL. A Pediatric Oncology Group (POG) study , 1999, Leukemia.

[30]  W. Kamps,et al.  Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: results of Dutch Childhood Leukemia Study Group Protocol ALL-7 (1988-1991). , 1999, Blood.

[31]  K. Gross,et al.  Disordered T-Cell Development and T-Cell Malignancies in SCL LMO1 Double-Transgenic Mice: Parallels with E2A-Deficient Mice , 1999, Molecular and Cellular Biology.

[32]  S. Burdach,et al.  A classification based on T cell selection-related phenotypes identifies a subgroup of childhood T-ALL with favorable outcome in the COALL studies , 1999, Leukemia.

[33]  W. Kamps,et al.  High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia. Results of protocol ALL VI from the Dutch Childhood Leukemia Study Group. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  H. Hsu,et al.  Formation of in vivo complexes between the TAL1 and E2A polypeptides of leukemic T cells. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[35]  A. Hagemeijer,et al.  Translocation of BCR to chromosome 9: A new cytogenetic variant detected by FISH in two Ph‐negative, BCR‐positive patients with chronic myeloid leukemia , 1993, Genes, chromosomes & cancer.

[36]  D. Littman,et al.  A heterodimer of HEB and an E12-related protein interacts with the CD4 enhancer and regulates its activity in T-cell lines , 1993, Molecular and cellular biology.

[37]  F. Behm,et al.  Clinical and biologic relevance of immunologic marker studies in childhood acute lymphoblastic leukemia. , 1993, Blood.

[38]  Y. Hayashi,et al.  Clinical significance of TAL1 gene alteration in childhood T-cell acute lymphoblastic leukemia and lymphoma. , 1993, Leukemia.

[39]  M. Amylon,et al.  Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study. , 1993, Blood.

[40]  J. V. van Dongen,et al.  Site-specific deletions involving the tal-1 and sil genes are restricted to cells of the T cell receptor alpha/beta lineage: T cell receptor delta gene deletion mechanism affects multiple genes , 1993, The Journal of experimental medicine.

[41]  S. Raimondi,et al.  Disruption of the SCL gene by a t(1;3) translocation in a patient with T cell acute lymphoblastic leukemia , 1992, The Journal of experimental medicine.

[42]  J. Ritz,et al.  Disruption of the SCL locus in T-lymphoid malignancies correlates with commitment to the T-cell receptor alpha beta lineage. , 1992, Blood.

[43]  P Berg,et al.  Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. , 1977, Journal of molecular biology.

[44]  C. Bloomfield,et al.  Cytogenetics of Acute Leukemia , 2013 .

[45]  J. V. van Dongen,et al.  Two dual-color split signal fluorescence in situ hybridization assays to detect t(5;14) involving HOX11L2 or CSX in T-cell acute lymphoblastic leukemia. , 2004, Haematologica.

[46]  Ching-Hon Pui,et al.  Acute lymphoblastic leukemia. , 2004, The New England journal of medicine.

[47]  J. Hermans,et al.  BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991–1996) , 2002, Leukemia.

[48]  E. Thiel,et al.  Incidence and prognostic significance of immunophenotypic subgroups in childhood acute lymphoblastic leukemia: experience of the BFM study 86. , 1993, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[49]  F. Prieto,et al.  [Cytogenetics in the acute leukemias]. , 1981, Sangre.