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18. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia

Author

Coustan Smith, E, Mullighan, C, Onciu, M, Behm, F, Raimondi, S, Pei, D, Cheng, C, Su, X, Rubnitz, J, Basso, G, Biondi, A, Pui, C, Downing, J, Campana, D, Mullighan, CG, Behm, FG, Raimondi, SC, Rubnitz, JE, Pui, CH, Downing, JR, Campana, D., BIONDI, ANDREA, Coustan Smith, E, Mullighan, C, Onciu, M, Behm, F, Raimondi, S, Pei, D, Cheng, C, Su, X, Rubnitz, J, Basso, G, Biondi, A, Pui, C, Downing, J, Campana, D, Mullighan, CG, Behm, FG, Raimondi, SC, Rubnitz, JE, Pui, CH, Downing, JR, Campana, D., and BIONDI, ANDREA

Abstract

Background: About a fifth of children with acute T-lymphoblastic leukaemia (T-ALL) succumb to the disease, suggesting an unrecognised biological heterogeneity that might contribute to drug resistance. We postulated that T-ALL originating from early T-cell precursors (ETPs), a recently defined subset of thymocytes that retain stem-cell-like features, would respond poorly to lymphoid-cell-directed therapy. We studied leukaemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome. Methods: Leukaemic cells from 239 patients with T-ALL enrolled at St Jude Children's Research Hospital (n=139) and in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000 (n=100) were assessed by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis. Probabilities of survival and treatment failure were calculated for subgroups considered to have ETP-ALL or typical T-ALL. Findings: 30 patients (12·6%) had leukaemic lymphoblasts with an ETP-related gene-expression signature or its associated distinctive immunophenotype (CD1a-, CD8-, CD5weak with stem-cell or myeloid markers). Cases of ETP-ALL showed increased genomic instability, in terms of number and size of gene lesions, compared with those with typical T-ALL. Patients with this form of leukaemia had high risk of remission failure or haematological relapse (72% [95% CI 40-100] at 10 years vs 10% [4-16] at 10 years for patients with typical T-ALL treated at St Jude Children's Research Hospital; and 57% [25-89] at 2 years vs 14% [6-22] at 2 years for patients treated in the AIEOP trial). Interpretation: ETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. Its early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management

Published
2009

19. Pathogenesis of an infectious mononucleosis-like disease induced by a murine gamma-herpesvirus: Role for a viral superantigen?

Author

Tripp, RA, HamiltonEaston, AM, Cardin, RD, Nguyen, P, Behm, FG, Woodland, DL, Doherty, PC, Blackman, MA, Tripp, RA, HamiltonEaston, AM, Cardin, RD, Nguyen, P, Behm, FG, Woodland, DL, Doherty, PC, and Blackman, MA

Abstract

The murine gamma-herpesvirus 68 has many similarities to EBV, and induces a syndrome comparable to infectious mononucleosis (IM). The frequency of activated CD8+ T cells (CD62L(lo)) in the peripheral blood increased greater than fourfold by 21 d after infection of C57BL/6J (H-2(b)) mice, and remained high for at least a further month. The spectrum of T cell receptor usage was greatly skewed, with as many as 75% of the CD8+ T cells in the blood expressing a Vbeta4+ phenotype. Interestingly, the Vbeta4 dominance was also seen, to varying extents, in H-2(k), H-2(d), H-2(u), and H-2(q) strains of mice. In addition, although CD4 depletion from day 11 had no effect on the Vbeta4 bias of the T cells, the Vbeta4+CD8+ expansion was absent in H-2IA(b)-deficient congenic mice. However, the numbers of cycling cells in the CD4 antibody-depleted mice and mice that are CD4 deficient as a consequence of the deletion of MHC class II, were generally lower. The findings suggest that the IM-like disease is driven both by cytokines provided by CD4+ T cells and by a viral superantigen presented by MHC class II glycoproteins to Vbeta4+CD8+ T cells.

Published
1997

48. Clinical significance of low levels of myeloperoxidase positivity in childhood acute nonlymphoblastic leukemia

Author

Pui, CH, Behm, FG, Kalwinsky, DK, Murphy, SB, Butler, DL, Dahl, GV, and Mirro, J

Abstract

The clinical significance of a low percentage of myeloperoxidase- positive blast cells in childhood acute nonlymphoblastic leukemia was determined. Of 155 consecutive cases studied by cytochemical staining methods, 14 were characterized by 4% to 15% (median 6%) myeloperoxidase- positive blasts. All 14 cases showed reactivity to Sudan black B stain, and 7 had Auer rods. The morphological subtypes of leukemia were M1 (8 cases), M2 (3), M4 (1), and M5 (2). Immunological marker studies disclosed the lymphoid-associated T11 antigen on cells from 8 of the 11 cases tested. Other lymphoid-related findings in these 8 cases included the T3 antigen and E rosette formation in 1 case each. Among cases that were prospectively studied for the expression of lymphoid-associated markers, 6 of 8 with low levels of myeloperoxidase positivity compared with only 1 of 44 with higher levels (greater than 15%) possessed such features (P less than 0.001). We conclude that low levels of myeloperoxidase reactivity distinguish cases of acute leukemia in which the blast cells coexpress lymphoid (T11 antigen) and myeloid markers.

Published
1987
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49. Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia

Author

Pui, CH, Williams, DL, Raimondi, SC, Rivera, GK, Look, AT, Dodge, RK, George, SL, Behm, FG, Crist, WM, and Murphy, SB

Abstract

Leukemic cells from 31 (7.6%) of 409 children with newly diagnosed acute lymphoblastic leukemia (ALL) had a hypodiploid karyotype. The patients' ages ranged from 0.8 to 17 years (median, 5 years) and their initial leukocyte counts from 1.0 to 132 X 10(9)/L (median, 12.7 X 10(9)/L). Modal chromosome numbers for the leukemic stem lines were 45 in 26 cases, 28 in two cases, and 26, 36 and 43 in one case each. Seven cases had one to three additional abnormal lines due to clonal evolution. Chromosome 20 was lost most frequently (nine cases). Structural abnormalities--including chromosomal translocations (21 cases), deletions (ten cases), duplications (two cases), or inversions (one case)--were common findings; the nonrandom translocations consisted of the t(1;19)(q23;p13.3) in two pre-B cases and tdic(9;12)(p1?1;p1?2) in three cases of common ALL. When compared with hyperdiploid cases (greater than 50 chromosomes), ALL with hypodiploidy was found to have a poorer outcome and was more likely to be associated with chromosomal translocations, higher serum lactic dehydrogenase levels, and age less than 2 or greater than or equal to 10 years. Moreover, patients with hypodiploid ALL fared as poorly as those with pseudodiploid karyotypes, even though their leukocyte counts and serum lactic dehydrogenase levels were lower and they had a comparable frequency of leukemic cell translocations. Hypodiploidy is therefore an unfavorable karyotypic feature in childhood ALL.

Published
1987
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50. Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia: association with high-risk clinical features

Author

Murphy, SB, Raimondi, SC, Rivera, GK, Crone, M, Dodge, RK, Behm, FG, Pui, CH, and Williams, DL

Abstract

To assess the frequency and significance of nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia (ALL), we analyzed our experience with 398 consecutive cases with completely banded karyotypes. Forty cases (10%) with abnormalities of 9p were identified: 26 with deletions, nine with unbalanced translocations resulting in the loss of 9p material, and five with apparently balanced reciprocal translocations. As compared with children with ALL lacking 9p abnormalities, these 40 cases were significantly older, had higher initial circulating WBC counts, more “lymphomatous” disease characteristics (including presence of a mediastinal mass in 15%. T- cell phenotype in 26%, splenomegaly greater than 8 cm in 25%), an increased failure rate in the first 2 to 3 years after diagnosis, and a higher incidence of extramedullary relapse. Conversely, lymphomatous ALL cases were twice as likely (19% v 8%) to have an abnormality of chromosome 9p than ALL cases lacking lymphomatous features (P = .01). The finding of an abnormal chromosome 9p, however, was not specific for lymphomatous ALL or T-cell lineage, because most cases were neither lymphomatous nor T-cell, and the overall Kaplan-Meier distribution of treatment failures for abnormal 9p cases was not statistically significantly different from control ALL cases receiving the same treatment who lacked abnormalities of 9p (P = .06, by log-rank test). We conclude that nonrandom abnormalities of chromosome 9p, especially a breakpoint in 9p21–22, occur with increased frequency in childhood ALL in association with some high-risk clinical features. Despite this association, the chromosome anomaly is nonspecific in its syndrome delineation and confers no major adverse consequence on long-term survival of childhood ALL treated with modern therapy. However, due to an apparently increased hazard of involvement of the CNS (eight of 17 failures), it may be inadvisable to lessen the intensity of CNS preventive therapy for this group of patients.

Published
1989
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