Screening for core binding factor gene rearrangements in acute myeloid leukemia

Grimwade, David

doi:10.1038/sj.leu.2402421

Cited by 20 publications

(11 citation statements)

References 33 publications

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“…14,15 Overall, previous studies suggest that up to 15% of AML with evidence of an underlying AML1-ETO or CBF␤-MYH11 gene fusion lack the typical respective cytogenetic abnormality (reviewed in Ref. 73), thereby providing an important rationale for molecular screening for such rearrangements. This could not only serve to increase the numbers of patients with a fusion gene target who could be monitored for MRD; but also identify those who would be suitable for tailored therapeutic approaches including molecularly targeted strategies, which are likely to play an increasing role in the management of leukemia patients in the future.…”

Section: 71mentioning

confidence: 99%

Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia

2002

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Acute promyelocytic leukemia (APL) is characterized by a number of features that underpin the need for rapid and accurate diagnosis and demand a highly specific treatment approach. These include the potentially devastating coagulopathy, sensitivity to anthracycline-based chemotherapy regimens, as well as unique responses to all-trans retinoic acid and arsenic trioxide that have revolutionized therapy over the last decade. The chromosomal translocation t(15;17) which generates the PML-RAR␣ fusion gene has long been considered the diagnostic hallmark of APL; however, this abnormality is not detected in approximately 10% cases with successful karyotype analysis. In the majority of these cases, the PML-RAR␣ fusion gene is still formed, resulting from insertion events or more complex rearrangements. These cases share the beneficial response to retinoids and favorable prognosis of those with documented t(15;17), underscoring the clinical relevance of molecular analyses in diagnostic refinement. In other cases of t(15;17) negative APL, various chromosomal rearrangements involving 17q21 have been documented leading to fusion of RAR␣ to alternative partners, namely PLZF, NPM, NuMA and STAT5b. The nature of the fusion partner has a significant bearing upon disease characteristics, including sensitivity to retinoids and arsenic trioxide. APL has provided an exciting treatment model for other forms of AML whereby therapeutic approach is directed towards cytogenetically and molecularly defined subgroups and further modified according to response as determined by minimal residual disease (MRD) monitoring. Recent studies suggest that rigorous MRD monitoring, coupled with preemptive therapy at the point of molecular relapse improves survival in the relatively small subgroup of PML-RAR␣ positive patients with 'poor risk' disease. Advent of 'real-time' quantitative RT-PCR technology seems set to yield further improvements in the predictive value of MRD assessment, achieve more rapid sample throughput and facilitate inter-and intralaboratory standardization, thereby enabling more reliable comparison of data between international trial groups. Leukemia (2002Leukemia ( ) 16, 1959Leukemia ( -1973 Clinical featuresAcute promyelocytic leukemia (APL) is associated with a number of features that emphasize the need for rapid and accurate diagnosis and demand a highly specific treatment approach. Of critical importance is the potentially severe coagulopathy that often accompanies the disease, which can induce thrombotic and more often hemorrhagic complications, that are the most prevalent clinical features at presentation. The coagulopathy is frequently triggered or further exacerbated by initiation of chemotherapy, and led to the demise of up to a quarter of patients in early studies. However, increased awareness of this problem, prompt initiation of ATRA-based therapy, together with improvements in supportive care have seen a reduction in induction death rates to approximately 10% or less in more recent clinical studies.

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Section: 71mentioning

confidence: 99%

Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia

2002

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“…After selection, the number of CGs was ultimately reduced to three, which were subjected to further analysis ( Figure 1 and Table 2). Oligonucleotide primers and probes were designed employing the GUS (7q21) 11 …”

Section: Primers and Probesmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8] The development of PCR methods has resulted in a more accurate diagnosis of balanced translocations, particularly in cases of cryptic translocations, which before were only detectable by molecular methods. [9][10][11] Although appropriate in the diagnostic setting, standard reverse transcriptase-polymerase chain reaction (RT-PCR) methods are less suitable for the evaluation of the disease status during clinical remission, that is detection of minimal residual disease (MRD). Qualitative RT-PCR determinations were therefore only of limited value in the longitudinal follow-up of acute leukemia patients, since many of these patients became PCR negative.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using ‘real-time’ quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) – a Europe against cancer program

et al. 2003

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Real-time quantitative RT-PCR (RQ-PCR) is a sensitive tool to monitor minimal residual disease (MRD) in leukemic patients through the amplification of a fusion gene (FG) transcript. In order to correct variations in RNA quality and quantity and to calculate the sensitivity of each measurement, a control gene (CG) transcript should be amplified in parallel to the FG transcript. To identify suitable CGs, a study group within the Europe Against Cancer (EAC) program initially focused on 14 potential CGs using a standardized RQ-PCR protocol. Based on the absence of pseudogenes and the level and stability of the CG expression, three genes were finally selected: Abelson (ABL), beta-2-microglobulin (B2M), and beta-glucuronidase (GUS). A multicenter prospective study on normal (n ¼ 126) and diagnostic leukemic (n ¼ 184) samples processed the same day has established reference values for the CG expression. A multicenter retrospective study on over 250 acute and chronic leukemia samples obtained at diagnosis and with an identified FG transcript confirmed that the three CGs had a stable expression in the different types of samples. However, only ABL gene transcript expression did not differ significantly between normal and leukemic samples at diagnosis. We therefore propose to use the ABL gene as CG for RQ-PCRbased diagnosis and MRD detection in leukemic patients. Overall, these data are not only eligible for quantification of fusion gene transcripts, but also for the quantification of aberrantly expressed genes.

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“…The kinetics of disappearance of molecular markers in AML are influenced by the various therapeutic regimens but are mainly different between the various types; for example, while molecular remission is achieved within the first 6 months in patients with acute promyelocytic leukemia, PCR markers may persist for several years in apparently cured patients with CBF leukemias [19, 26, 36, 37]. …”

Section: Detection Of Mrd In Aml With Genetic Abnormalities By Nucleimentioning

confidence: 99%

“…Currently, 40–50% of AML patients have a specific marker detectable by PCR techniques. The major specific molecular markers with an expected frequency of >1% in de novo unselected AML patients are involvement of the MLL gene on chromosome band 11q23 with about 50 partners (10–20%) [19, 24, 25]followed by the core binding factor (CBF) leukemias with AML1/ETO (7–14%) and CBFβ/MYH11 (3–10%) rearrangements [19, 26]. PML/RARα and variant rearrangements (PLZF) reviewed elsewhere in this issue are confined to acute promyelocytic leukemia and occur in 5–10% of de novo AML [19, 27, 28].…”

Section: Detection Of Mrd In Aml With Genetic Abnormalities By Nucleimentioning

confidence: 99%

Detection of Minimal Residual Disease in Acute Myelogenous Leukemia

Raanani¹,

Ben‐Bassat²

2004

Acta Haematol

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Acute myelogenous leukemia (AML) is considered to be in complete remission when fewer than 5% of the cells in bone marrow are blasts. Nevertheless, approximately two thirds of patients relapse due to persisting leukemic blasts. The persistence of these cells, below the threshold of morphological detection, is termed minimal residual disease (MRD) and various methods are used for its detection. These methods include classical cytogenetics, fluorescence in situ hybridization, qualitative and quantitative RT-PCR and multiparametric flow cytometry. Currently, less than half of the AML patients have a specific marker detectable by RT-PCR techniques. The major specific molecular markers are involvement of the MLL gene with up to 50 different partners and partial tandem duplications, the core binding factor leukemias with AML1/ETO and CBFβ/MYH11 rearrangements, PML/RARα in acute promyelocytic leukemia, internal tandem duplications and mutations of FLT3 and some other rare translocations. In addition, several other genes show abnormal expression levels in AML, including the Wilms tumor gene, the PRAME gene and Ig/TCR rearrangements. Most of these genetic abnormalities can be detected by qualitative but more importantly by quantitative RT-PCR. The kinetics of disappearance of molecular markers in AML differs between the various types of leukemias, although at least a 2 log reduction of transcript after induction chemotherapy is necessary for long-term remission in all types. Conversely, the change of PCR from negativity to positivity is highly predictive of relapse. Whereas in acute lymphoblastic leukemia, multiparametric flow cytometry is an established method for MRD detection, this is less so in AML. The reason is the absence of well-characterized leukemia-specific antigens and the existence of phenotypic changes at relapse. On the other hand, this method is convenient due to its simplicity and universal applicability. In conclusion, several methods can be used for MRD detection in AML patients; each has its pros and cons. Several issues still remain to be settled including the choice of the best method and the timing for MRD monitoring and above all the practical clinical implications of MRD in the various types of AML.

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Screening for core binding factor gene rearrangements in acute myeloid leukemia

Cited by 20 publications

References 33 publications

Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia

Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia

Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using ‘real-time’ quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) – a Europe against cancer program

Detection of Minimal Residual Disease in Acute Myelogenous Leukemia

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