Establishing the presence of the t( 15; 17) in suspected acute promyelocytic leukaemia: cytogenetic, molecular and PML immunofluorescence assessment of patients entered into the M.R.C. ATRA trial

@article{Grimwade1996EstablishingTP,
  title={Establishing the presence of the t( 15; 17) in suspected acute promyelocytic leukaemia: cytogenetic, molecular and PML immunofluorescence assessment of patients entered into the M.R.C. ATRA trial},
  author={David Grimwade and Kathy Howe and Stephen Langrbeer and L Davis and Fiona Oliver and Helen Walker and David M Swirsky and Keith Wheatley and Anthony H. Goldstone and Alan K Burnett and E. Solomon},
  journal={British Journal of Haematology},
  year={1996},
  volume={94}
}
Detection of the t(15;17) or its molecular consequence, the PML-RAR alpha rearrangement, is critical for meaningful analysis of clinical trials involving patients with suspected acute promyelocytic leukaemia (APL). Its presence remains the best predictor of a favourable response to retinoids, such as ATRA, which in combination with chemotherapy confer significant improvements in disease-free survival. We have evaluated the relative efficacy of RT-PCR, cytogenetics and PML immunofluorescence… 

Identification of the t(15;17) in AML FAB types other than M3: evaluation of the role of molecular screening for the PML/RARalpha rearrangement in newly diagnosed AML. The Medical Research Council (MRC) Adult Leukaemia Working Party.

Routine molecular screening for PML/RARalpha rearrangements is not justified and should be reserved for those cases displaying features which may be suspicious of APL even if such cells comprise only a minority of the total population.

The significance of minimal residual disease in patients with t(15;17).

  • D. Grimwade
  • Medicine, Biology
    Best practice & research. Clinical haematology
  • 2002
Overall, these studies undertaken within the context of a relatively homogeneous disease entity confirm that MRD monitoring provides independent prognostic information, serving as a valuable model for improving treatment strategy in other molecularly defined subsets of acute myeloid leukaemia (AML).

Identification of the t(15;17) in AML FAB types other than M3: evaluation of the role of molecular screening for the PML/RARα rearrangement in newly diagnosed AML

This study demonstrates that the t(15;17) is not restricted to patients with M3 morphology as defined by current FAB criteria, and suggests that routine molecular screening for PML/RARα rearrangements is not justified and should be reserved for those cases displaying features which may be suspicious of APL.

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 (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

Acute promyelocytic leukaemia with t(11;17)(q23;q12‐21) and a good initial response to prolonged ATRA and combination chemotherapy

A case of AML FAB type M3 with the translocation t(11;17)(q23;q21) leading to a PLZF/RARα rearrangement is described who entered morphological and cytogenetic complete remission after concurrent prolonged ATRA and one course of induction chemotherapy and remains in Morphological and molecular remission at 10 months after presentation.

Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the Randomized MRC Trial.

All-trans retinoic acid (ATRA) is an essential component of the treatment of acute promyelocytic leukemia, but the optimal timing and duration remain to be determined and a positive RT-PCR after consolidation identifies patients at a higher risk of relapse.

Pathogenesis, Diagnosis and Monitoring of Residual Disease in Acute Promyelocytic Leukaemia

Quantitative RT-PCR technology is expected to further improve the predictive value of MRD monitoring and therefore to guide therapy in order to reduce the rate of relapses and to increase rates of cure in high-risk patients.

Acute promyelocytic leukemia lacking t(15;17): molecular evidence of atypical PML/RAR- α transcriptional variant by gene sequencing Akutna promijelocitna leukemija bez t(15;17): molekularni dokazi atipi č ne PML/RAR- α transkripcione varijante genskim sekvenciranjem

The findings with the additional review of the literature, em-phasizes the importance of detailed identification of atypical PML/RAR- α fusions, not only for the purpose of knowing their role in leukemogenesis, but also for the assessment of the impact that they can have on the outcome of the treatment.
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References

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Minimal residual disease detection in acute promyelocytic leukemia by reverse-transcriptase PCR: evaluation of PML-RAR alpha and RAR alpha-PML assessment in patients who ultimately relapse.

This study demonstrates that treatment strategies involving determination of PCR status post-consolidation, even using RAR alpha-PML in addition to the more conventional PML-RAR alpha assay will fail to identify all patients at risk of relapse.

Diagnosis of acute promyelocytic leukaemia by RT‐PCR: detection of PML‐RARA and RARA‐PML fusion transcripts

Reverse transcription coupled with the polymerase chain reaction (RT‐PCR) has been used to develop a diagnostic test for APL based on the PML‐RARA fusion message, which suggests that it is the 15q + derivative which mediates leukaemogenesis.

Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17).

APL associated with t(11;17) and fusion of the PLZF and RAR alpha genes is a discrete clinico-pathologic syndrome with a distinctly worse prognosis than t(15;17), and six patients failed to achieve complete remission after initial chemotherapy or differentiation therapy with all-trans retinoic acid (ATRA).

Molecular analysis of simple variant translocations in acute promyelocytic leukemia

An absolute requirement for the rearrangement of the RAARA gene in the pathogenesis of APL is indicated and the importance of RARA during normal myeloid differentiation is underline.

Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid.

Exposure to the type "A" isoform of PML/RAR-alpha was associated with a significantly shorter duration of relapse-free and overall survival and basal expression of CD13 (aminopeptidase N), a cell surface enzyme previously linked to tumor cell invasion and an inferior outcome in patients with acute myeloid leukemia, was highly associated with both development of the syndrome.

Cytogenetic Studies in Acute Promyelocytic Leukemia: A Survey of Secondary Chromosomal Abnormalities

Cytogenetic studies performed on 19 patients treated with all‐trans retinoic acid did not indicate that this treatment induces chromosomal abnormalities, and the typical t( 15; 17) or variants of this translocation were observed in all but four patients.

Karyotypically defined risk groups in acute myeloid leukaemia.

Analysis of the joining sequences of the t(15;17) translocation in human acute promyelocytic leukemia: Sequence non‐specific recombination between the pml and rara genes within identical short stretches

Data provide a potential model of the t(15;17) translocation: random DNA double strand cleavage, modification of DNA ends by enzymes including terminal deoxynucleotidyl transferase, and single strand base‐pairing within identical short stretches.

Persistence of RARa‐PML fusion mRNA detected by reverse transcriptase polymerase chain reaction in patients in long‐term remission of acute promyelocytic leukaemia

R reverse transcriptase polymerase chain reaction (RT‐PCR) is used to detect both fusion transcripts serially in 18 patients in remission of APL after chemotherapy and bone marrow transplantation, finding that RARa‐PML was consistently detected.

The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion.

This case defines a third class of APL rearrangements, all of which generate fusion proteins of RARA, which are expressed in the patient's leukemic cells, along with wild-type RARA derived from the uninvolved allele.
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