Multilineage involvement of Philadelphia chromosome positive acute lymphoblastic leukemia

Schenk, Thomas; Keyhani, Afsaneh; Böttcher, Sebastian; Kliche, Kay Oliver; Goodacre, Angela; Guo, Jie; Arlinghaus, Ralph B.; Kantarjian, Hagop; Andreeff, Michael

doi:10.1038/sj.leu.2400986

Cited by 48 publications

(39 citation statements)

References 8 publications

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“…The published studies usually refer to a limited number of patients and draw different conclusions, but at least in a subset of patients, multilineage involvement has been clearly demonstrated. [40][41][42][43][44][45] We were able to analyse sorted cell populations from a follow-up sample in one of the recent cases with m-BCR/ABL expression (UPN1092) and we conclusively show that although the clonal Ig/TCR rearrangements are present only in the leukaemic cells, the BCR/ ABL fusion gene is found also in a subset of non-malignant B cells and in myeloid lineage. The data demonstrate that BCR/ ABL fusion as the first or early hit in leukaemogenesis arises in a progenitor cell with ability to differentiate into multiple haematopoietic lineages.…”

Section: Discussionmentioning

confidence: 99%

Quantification of fusion transcript reveals a subgroup with distinct biological properties and predicts relapse in BCR/ABL-positive ALL: implications for residual disease monitoring

et al. 2009

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Minimal residual disease (MRD) monitoring is an essential tool for risk group stratification in current treatment protocols for childhood acute lymphoblastic leukaemia (ALL). Although quantitative detection of clonal immunoglobulin (Ig) and T-cell receptor (TCR ) gene rearrangements is currently considered to be the standard method, leukaemia fusion genes provide other possible targets for MRD follow-up, as already demonstrated in TEL/AML1-positive ALLs. We analysed and compared MRD levels quantified by BCR/ABL transcript detection and by the standard Ig/TCR-based method in 218 bone marrow specimens from 17 children with BCR/ABL-positive ALL. We found only a limited overall correlation of MRD levels as assessed by the two methods (correlation coefficient R 2 ¼ 0.64). The correlation varied among patients from excellent (R 2 ¼ 0.99) to very poor (R 2 ¼ 0.17). Despite identical sensitivity of the approaches, 20% of the samples were negative by the Ig/TCR approach whereas positive by the BCR/ABL method. We show that multilineage involvement is at least partly responsible for the discrepancy. Moreover, our data demonstrate that BCR/ABL monitoring enables better and earlier prediction of relapse compared to the standard Ig/TCR methodology. We conclude that BCR/ABLbased MRD monitoring of childhood ALL is a clinically relevant tool and should be performed in parallel with the standard Ig/ TCR follow-up.

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Section: Discussionmentioning

confidence: 99%

Quantification of fusion transcript reveals a subgroup with distinct biological properties and predicts relapse in BCR/ABL-positive ALL: implications for residual disease monitoring

et al. 2009

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“…However, recent work has shown the presence of the Ph chromosome in lineages other than lymphoid in Phpositive ALL, suggesting that leukemogenesis in Ph-positive ALL affects an early noncommitted progenitor cell, similarly to what occurs in CML. 22 The mechanism that leads to clinical expression of the disease in only lymphoid lines is still not known.…”

Section: Discussionmentioning

confidence: 99%

ABL1 methylation in Ph-positive ALL is exclusively associated with the P210 form of BCR-ABL

et al. 2001

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In human Ph-positive leukemia there is a clear association of different forms of the BCR-ABL oncogene with distinct types of leukemia. The P190 form of BCR-ABL is rarely observed in chronic myeloid leukemia (CML) but is present in 50% of Phpositive acute lymphoblastic leukemia (ALL). In contrast, the P210 form is observed both in CML and 50% of Ph-positive ALL. Methylation of the proximal promoter of the ABL1 gene has been shown to be a nearly universal event associated with clinical progression of CML. This raises the question of whether methylation of the ABL1 promoter is an epigenetic modification also associated with Ph-positive ALL. To study this issue, we used methylation-specific PCR and bisulfite sequencing to determine the methylation status of the ABL1 promoter in 18 Ph-positive ALL samples. We report here that gene-specific ABL1 promoter methylation is associated mainly with the P210 form of BCR-ABL and not the P190 form. While six out of the seven P210-positive ALL samples had ABL1 promoter methylation, none of the 11 P190-positive ALL samples demonstrated ABL1 promoter methylation. In addition, we estimated the extent and relative abundance of ABL1 promoter methylation in several Ph-positive ALL samples and compared it to the methylation pattern in chronic, accelerated and blastic crisis phases of CML. We put forth a model that correlates the different types of leukemias with the different levels of ABL1 promoter methylation. Leukemia (2001) 15, 575-582.

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“…The designs of the SF and the ES probes allow detection of breakpoints involving the m-bcr of the BCR gene as well as the BCR/ABL fusion. 17,18 The interphase FISH patterns expected with each probe are shown in Table 1. For those cases with standard and nonstandard signal patterns observed in interphase, the number and relative size of the signals were confirmed, where possible, on representative metaphase cells from the same samples.…”

Section: Fishmentioning

confidence: 99%

Derivative chromosome 9 deletions are a significant feature of childhood Philadelphia chromosome positive acute lymphoblastic leukaemia

et al. 2005

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Deletions from the derivative chromosome 9, der(9), of the translocation, t(9;22)(q34;q11), at the site of the ABL/BCR fusion gene, have been demonstrated by fluorescence in situ hybridisation (FISH), in both Philadelphia chromosome (Ph)-positive chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL). In CML they occur in 10-15% of cases and appear to indicate a worse prognosis, whereas in ALL, the situation is unclear. This study presents the findings of dual fusion FISH used to detect such deletions in a series of 27 BCR/ ABL-positive childhood ALL patients. Metaphase FISH was essential for the accurate interpretation of interphase FISH signal patterns. Three cases (11%) had a single fusion signal, resulting from deletions of the der(9). Three other patients with variant translocations and one with an insertion, also had a single fusion, but with no evidence of deletions. Gain of a fusion in approximately one-third of patients indicated a second Ph, which appears to be a diagnostic marker of Phpositive ALL. This study shows that the incidence of deletions from the der(9) in childhood ALL is at least as high as that reported for CML.

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Multilineage involvement of Philadelphia chromosome positive acute lymphoblastic leukemia

Cited by 48 publications

References 8 publications

Quantification of fusion transcript reveals a subgroup with distinct biological properties and predicts relapse in BCR/ABL-positive ALL: implications for residual disease monitoring

Quantification of fusion transcript reveals a subgroup with distinct biological properties and predicts relapse in BCR/ABL-positive ALL: implications for residual disease monitoring

ABL1 methylation in Ph-positive ALL is exclusively associated with the P210 form of BCR-ABL

Derivative chromosome 9 deletions are a significant feature of childhood Philadelphia chromosome positive acute lymphoblastic leukaemia

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