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Myeloid lineage involvement in BCR/ABL-positive acute lymphoblastic leukaemia
Hovorková, Lenka ; Zuna, Jan (advisor) ; Mikyšková, Romana (referee)
The Philadelphia chromosome has been discovered in 1960. This chromosomal aberration was mistakenly associated only with chronic myeloid leukaemia (CML) for decade. However, this type of translocation including chromosomes 9 and 22 was found in patients with different type of neoplasia - acute lymphoblastic leukaemia (ALL). Different lineage involvement has been found in these two types of leukaemia. Whereas in Ph-positive ALL, the Philadelphia chromosome is restricted to the lymphoid lineage, in CML patients mostly myeloid cells are those being Ph-positive. Hence it seems quite trivial to distinguish between ALL and CML. But there is a phase of CML called lymphoid blast crisis which is indistinguishable from ALL. The possibility of distinguishing between CML in lymphoid blast crisis and ALL would inhere in determining myeloid lineage involvement. Actually it had been shown that some patients with Ph+ ALL have involved also a myeloid lineage. Different types of treating protocols are used in CML and ALL. In addition, prognoses for both types of leukaemia are different. Thus it is crucial to distinguish between this two disorders and revealing of any difference can impact the treatment outcome of above mentioned malignancies. Detection of minimal residual disease according to involvement of myeloid or CD34+...
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Leukaemias with BCR/ABL fusion gene.
Hovorková, Lenka ; Zuna, Jan (advisor) ; Zemanová, Karla (referee)
Philadelphia (Ph) chromosome, as a result of reciprocal translocation, is in majority of cases connected to two types of leukaemia - chronic myelogenous (CML) and acute lymphoblastic (ALL). The translocation occurs within large intronic sequences of BCR and ABL genes. The breakpoints are specific for individual patient and may be used as a target for monitoring of leukemic burden (MRD, minimal residual disease) during the treatment. In general, MRD is an important prognostic factor, which influences the treatment intensity. Two standardized methods are currently used for its monitoring. The first one is based on the detection of clonal specific Immunoglobulin and/or T-cell receptor genes rearrangements (and thus cannot be used for CML cases) at the DNA level, the second one utilizes detection of the BCR/ABL fusion gene at the mRNA level. Our aim was to optimize and standardize the process to find individual patient breakpoints on Ph chromosome and to use it for MRD quantification. We found the breakpoint in 80 % cases. The MRD data from 15 patients obtained by our method were compared to the levels obtained by standard methods (Ig/TCR and BCR/ABL transcript quantification). In all but 1 patient we found significant discrepancies, raising the questions about leukemic origin and the most accurate method for...
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Pathogenesis of childhood leukemia
Hovorková, Lenka ; Zuna, Jan (advisor) ; Kolenová, Alexandra (referee) ; Jarošová, Marie (referee)
BCR-ABL1 fusion gene is a hallmark of chronic myeloid leukaemia (CML), but can be found also in patients with acute lymphoblastic leukaemia (ALL). In BCR-ABL1-positive ALL, two principal approaches for treatment response and minimal residual disease (MRD) monitoring are routinely used - quantification of genomic clonal rearrangements of immunoglobulin/T-cell receptor genes (Ig/TCR) and BCR-ABL1 expression. We established methods for determination of BCR-ABL1 genomic fusion and used the intronic breakpoints to measure MRD levels also at the BCR-ABL1 DNA level. Comparison of MRD based on Ig/TCR and genomic BCR-ABL1 in 47 consecutive childhood patients showed poor correlation in about 25 % cases with significantly higher BCR-ABL1 levels. In those patients, we found the BCR-ABL1 not only in ALL-blasts, but also in other cell subtypes (T-cells, myeloid cells) negative for clonal Ig/TCR rearrangements. For the similarity with CML we assigned this new leukaemia subtype with multilineage BCR- ABL1 involvement "CML-like" leukaemia. Our ongoing study is focused on the prognostic implications of discordant MRD results. As we characterized the genomic BCR-ABL1 fusion in 428 patients (which is to our knowledge the largest cohort described so far), we also analysed the origin of the breakpoints. Our data suggest...
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Leukaemias with BCR/ABL fusion gene.
Hovorková, Lenka ; Zuna, Jan (advisor) ; Zemanová, Karla (referee)
Philadelphia (Ph) chromosome, as a result of reciprocal translocation, is in majority of cases connected to two types of leukaemia - chronic myelogenous (CML) and acute lymphoblastic (ALL). The translocation occurs within large intronic sequences of BCR and ABL genes. The breakpoints are specific for individual patient and may be used as a target for monitoring of leukemic burden (MRD, minimal residual disease) during the treatment. In general, MRD is an important prognostic factor, which influences the treatment intensity. Two standardized methods are currently used for its monitoring. The first one is based on the detection of clonal specific Immunoglobulin and/or T-cell receptor genes rearrangements (and thus cannot be used for CML cases) at the DNA level, the second one utilizes detection of the BCR/ABL fusion gene at the mRNA level. Our aim was to optimize and standardize the process to find individual patient breakpoints on Ph chromosome and to use it for MRD quantification. We found the breakpoint in 80 % cases. The MRD data from 15 patients obtained by our method were compared to the levels obtained by standard methods (Ig/TCR and BCR/ABL transcript quantification). In all but 1 patient we found significant discrepancies, raising the questions about leukemic origin and the most accurate method for...
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Myeloid lineage involvement in BCR/ABL-positive acute lymphoblastic leukaemia
Hovorková, Lenka ; Zuna, Jan (advisor) ; Mikyšková, Romana (referee)
The Philadelphia chromosome has been discovered in 1960. This chromosomal aberration was mistakenly associated only with chronic myeloid leukaemia (CML) for decade. However, this type of translocation including chromosomes 9 and 22 was found in patients with different type of neoplasia - acute lymphoblastic leukaemia (ALL). Different lineage involvement has been found in these two types of leukaemia. Whereas in Ph-positive ALL, the Philadelphia chromosome is restricted to the lymphoid lineage, in CML patients mostly myeloid cells are those being Ph-positive. Hence it seems quite trivial to distinguish between ALL and CML. But there is a phase of CML called lymphoid blast crisis which is indistinguishable from ALL. The possibility of distinguishing between CML in lymphoid blast crisis and ALL would inhere in determining myeloid lineage involvement. Actually it had been shown that some patients with Ph+ ALL have involved also a myeloid lineage. Different types of treating protocols are used in CML and ALL. In addition, prognoses for both types of leukaemia are different. Thus it is crucial to distinguish between this two disorders and revealing of any difference can impact the treatment outcome of above mentioned malignancies. Detection of minimal residual disease according to involvement of myeloid or CD34+...
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