APML acute promyelocytic leukemia AML M3

AML M3 is associated with a balanced translocation between chromosomes 15 and 17, resulting in t(15;17)(q22;q21) and leading to rearrangement of the RARa gene (also termed RARA) on chromosome 17 and PML on chromosome 15 (Figure 6.10). With rearrangement of DNA, the chromosomal translocation produces two novel fusion genes involving PML and RARa, namely PML/RARaand RARa/PML. It is believed that PML/RARa is responsible for the development of aberrant hematopoiesis. There are two isoforms of the PML/RARa fusion gene: long and short. Patients who possess the short isoform have a poorer clinical outcome than those in whom the long isoform is found, but the exact mechanism involved is unclear at present.

The resultant fusion protein (PML/RARa) contains functional domains in both PML and RARa, and binds all-trans retinoic acid (ATRA), to which the leukemic cells in AML M3 are exquisitely sensitive. In fact ATRA, which induces differentiation of the leukemic cells, may alone achieve remission in 80% of de novo cases of AML M3. Two classes of retinoic acid receptor mediate the effects of retinoids: RAR and RXR, both of which are members of a superfamily of related ligand-inducible transcriptional regulatory factors. RAR (a, P and y) are activated by ATRA and 9-cis retinoic acid. RXR (a, P and Y) is activated by 9-cis retinoic acid only.

Patients with APML and t(15;17) who achieve remission are now regarded as good-risk patients, with a 60% chance of achieving long-term remission. The presence of the fusion gene may be inferred from cytogenetic analysis (i.e. the presence of typical translocation) or, more recently, by an RT-PCR method. In this, the PML/RARamRNA is reverse-transcribed into cDNA, which is then used for PCR detection of the abnormal transcript. The RT-PCR assay has been used to quan-titate residual leukemic cells in patients with M3 undergoing chemotherapy.

Trial data suggest that persistence of t(15;17) determined by the PCR approach predicts outcome: those patients who fail to become PCR-negative or who become PCR-positive following a period of PCR negativity subsequently suffer overt clinical relapse. More recent data have suggested that quantitative PCR monitoring of PML/RARa can identify patients at high risk of relapse and suggest that clinically practical monitoring at more frequent intervals may improve predictive accuracy for relapse or continuing complete remission in many patients with persistent, fluctuating MRD levels.

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