Diagnosis:
Acute Promyelocytic leukemia
• The t(15;17)(q22;q21) translocation resulting in the PML-RARA fusion is the most common translocation seen in acute promyelocytic leukemia (APL).
• Other translocations include t(11;17)(q23;q21) resulting in the ZBTB16-RARA (PLZF-RARA) fusion; t(5;17)(q35;q12-21) causing the NPM1-RARA (NPM-RARA) fusion; t(11;17)(q13;q21) with the NUMA1-RARA (NuMA-RARA) fusion; and der(17) effecting the STAT5B-RARA fusion (common/older terminology in parentheses).
• The PML-RARA fusion protein retains the DNA-binding and retinoic acid (RA)-binding domains of RAR-α, and the zinc finger and proline-rich domains of PML. In addition to inhibiting PML and RAR-α function, the fusion protein binds corepressors to recruit histone deacetylase (HDAC) to RA response genes, causing chromatin condensation and inhibiting transcription of these genes, resulting in differentiation arrest at the promyelocyte stage.
• Pharmacologic doses of all-trans retinoic acid (ATRA) inhibit this binding, and restore transcription of RA-responsive genes with differentiation and, ultimately, cell death.
• The PLZF (promyelocytic leukemia zinc finger)–RAR-α fusion protein contains a second, ATRA-resistant, corepressor binding site in the amino-terminal portion of PLZF, leading to resistance to treatment with ATRA. In addition, PLZF translocation positive cells are also resistant to arsenic trioxide (ATO), which is now used in conjunction with ATRA. In this setting, the use of HDAC inhibitors can partially reverse the resistance to ATRA and cause terminal differentiation.
• Because of the variability of chromosomal breakpoints, DNA polymerase chain reaction (PCR) for this translocation is not practical; RT-PCR and FISH are used most often.
• Retinoic acid derivatives when used alone do not result in loss of detectable transcript, although following consolidation chemotherapy most responders become RT-PCR negative, and loss of transcript is predictive of long-term survival.
