Translocation and Hybrid Gene Formation in Acute Promyelocytic Leukemia
The translocation t(15;17)(q22;q21) resulting in the PML-RARA fusion gene is exclusively found in acute promyelocytic leukemia (APL), making option B the correct answer.
Genetic Basis of APL
Acute promyelocytic leukemia is defined by the presence of the t(15;17)(q22;q21) translocation, which creates the characteristic PML-RARA fusion gene 1. This genetic abnormality is considered pathognomonic for APL and distinguishes it from other subtypes of acute myeloid leukemia (AML).
The translocation involves:
- The promyelocytic leukemia (PML) gene on chromosome 15q22
- The retinoic acid receptor alpha (RARA) gene on chromosome 17q21
This fusion creates two reciprocal fusion genes:
- PML-RARA on the derivative chromosome 15
- RARA-PML on the derivative chromosome 17
Distinguishing APL from Other Genetic Abnormalities
The other translocations mentioned in the question are associated with different AML subtypes or other leukemias:
t(4;11) AF4-MLL: Associated with acute lymphoblastic leukemia (ALL), particularly in infants, not APL 1.
t(8;21) AML1-ETO (RUNX1-RUNX1T1): Associated with AML with maturation (formerly M2), not APL 1.
t(9;22) BCR-ABL: Primarily associated with chronic myeloid leukemia (CML) and some cases of ALL. While rarely found in AML, it is not associated with APL 1.
Diagnostic Implications
The identification of t(15;17) and PML-RARA has critical diagnostic and therapeutic implications:
- It confirms the diagnosis of APL regardless of blast percentage in peripheral blood or bone marrow 1.
- It predicts response to all-trans retinoic acid (ATRA) and arsenic trioxide therapy 1.
- It allows for molecular monitoring of minimal residual disease.
Variant and Masked Translocations
While the classic t(15;17) is most common, several variants exist:
- Complex translocations involving chromosomes 15,17, and additional chromosomes 2.
- Cryptic or masked translocations where PML-RARA fusion occurs despite normal-appearing chromosomes 15 and 17 3, 4.
- Rare variant translocations involving RARA with partner genes other than PML (e.g., PLZF, NPM, NUMA, or STAT5B) 1.
Despite these variants, the presence of PML-RARA fusion remains the molecular hallmark of APL, making the t(15;17) translocation the defining genetic abnormality of this disease.
Clinical Significance
The PML-RARA fusion protein disrupts normal retinoid signaling and blocks myeloid differentiation at the promyelocyte stage 5, 6. Understanding this molecular mechanism has led to targeted therapies that induce differentiation of leukemic promyelocytes, revolutionizing APL treatment and dramatically improving survival rates.