| 1. |
- Li, Aihong, et al.
(författare)
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Distinctive IGH gene segment usage and minimal residual disease detection in infant acute lymphoblastic leukaemias.
- 2005
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 131:2, s. 185-92
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Tidskriftsartikel (refereegranskat)abstract
- Infant acute lymphoblastic leukaemia (ALL) represents a rare but unique subset with poor prognosis. We analysed mixed-lineage leukaemia (MLL) gene rearrangements and the sequences of complete and incomplete immunoglobulin heavy chain gene rearrangements (IGH) in 14 infants (age < or = 12 months at diagnosis) enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. The dynamics of the leukaemic clone were followed during the course of the disease by quantitative real-time polymerase chain reaction of IGH rearrangements. Sixteen sequences were obtained from 13 (93%) of these infants. There was marked over usage of the V(H)6.1 gene segment (64%) in infants compared with older children with ALL (8%), (P < 0.001) and overusage of D(H)6 (P = 0.004) and J(H)1 (P = 0.004). Poor outcome was associated with MLL gene rearrangements rather than any specific V(H)D(H)J(H) gene usage patterns. Levels of minimal residual disease (MRD) at the end of induction appeared to be high in infants with ALL compared with older children, and although the number of infant cases studied was small, there were no differences in MRD levels after induction therapy in infant ALL with or without MLL gene rearrangements (P = 0.41) and quantitative MRD assessment at the early time points may not be predictive of outcome. Novel treatment strategies are required to improve the outcome in this poor prognosis subset of children with ALL.
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| 2. |
- Li, Aihong, et al.
(författare)
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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.
- 2004
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 103:12, s. 4602-9
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Tidskriftsartikel (refereegranskat)abstract
- Sequence analysis of the immunoglobulin heavy chain genes (IgH) has demonstrated preferential usage of specific variable (V), diversity (D), and joining (J) genes at different stages of B-cell development and in B-cell malignancies, and this has provided insight into B-cell maturation and selection. Knowledge of the association between rearrangement patterns based on updated databases and clinical characteristics of pediatric acute lymphoblastic leukemia (ALL) is limited. We analyzed 381 IgH sequences identified at presentation in 317 children with B-lineage ALL and assessed the V(H)D(H)J(H) gene utilization profiles. The D(H)J(H)-proximal V(H) segments and the D(H)2 gene family were significantly overrepresented. Only 21% of V(H)-J(H) joinings were potentially productive, a finding associated with a trend toward an increased risk of relapse. These results suggest that physical location at the V(H) locus is involved in preferential usage of D(H)J(H)-proximal V(H) segments whereas D(H) and J(H) segment usage is governed by position-independent molecular mechanisms. Molecular pathophysiology appears relevant to clinical outcome in patients who have only productive rearrangements, and specific rearrangement patterns are associated with differences in the tumor biology of childhood ALL.
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| 3. |
- Zhou, Jianbiao, et al.
(författare)
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Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01.
- 2007
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 110:5, s. 1607-11
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Tidskriftsartikel (refereegranskat)abstract
- In a prospective trial in 284 children with B-lineage acute lymphoblastic leukemia (ALL), we assessed the clinical utility of real-time quantitative polymerase chain reaction analysis of antigen receptor gene rearrangements for detection of minimal residual disease (MRD) to identify children at high risk of relapse. At the end of induction therapy, the 5-year risk of relapse was 5% in 176 children with no detectable MRD and 44% in 108 children with detectable MRD (P < .001), with a linear association of the level of MRD and subsequent relapse. Recursive partitioning and clinical characteristics identified that the optimal cutoff level of MRD to predict outcome was 10(-3). The 5-year risk of relapse was 12% for children with MRD less than one leukemia cell per 10(3) normal cells (low MRD) but 72% for children with MRD levels greater than this level (high MRD) (P < .001) and children with high MRD had a 10.5-fold greater risk of relapse. Based upon these results we have altered our treatment regimen for children with B-lineage ALL and children with MRD levels greater than or equal to 10(-3) at the end of 4 weeks of multiagent induction chemotherapy now receive intensified treatment to attempt to decrease their risk of subsequent relapse.
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