The genetic hallmark of acute promyelocytic leukemia (APL) is the
balanced reciprocal chromosomal translocation of (15;17) leading to a
fusion of the promyelocytic leukemia (PML) gene on chromosome 15 and the
retinoic acid receptor-á (RARá) gene on chromosome 17 .
Identification of PML/RARá fusion gene by reverse
transcriptase-polymerase chain reaction (RT-PCR) without evidence of
t(15;17) both on conventional karyotype and fluorescence in situ
hybridization (FISH) is rare [2,3].
An 8-year-old girl was admitted with the complaints
of fever and generalized weakness for last 1˝ month, and epistaxis and
bleeding from gums for last 20 days. She had moderate pallor and
hepatosplenomegaly. Routine blood examination revealed hemoglobin 7.4 g/dL,
total white cell count 9.8×10/L.
Peripheral blood smear showed 35% neoplastic promyelocytes with
cytoplasmic hypergranulation. Coagulation profile revealed normal
prothrombin time and activated partial thromboplastin time, but serum
fibrinogen level was low. Bone marrow aspiration showed a hypercellular
marrow with 66% neoplastic promyelocytes and presence of multiple Auer
rods (faggot cells).
Cytochemical staining with myeloperoxidase was
strongly positive. Child was diagnosed morphologically as AML-M3 (hypergranular
variant). Immunophenotyping analysis of the bone marrow cells was
consistent with APL. Conventional cytogenetic analysis showed 46, XY,
isochromosome (17q). FISH analysis was negative for t(15;17). RT-PCR was
positive for PML–RARá fusion transcripts. She had completed both
induction and consolidation phase of all-trans retinoic acid (ATRA)
based chemotherapy regimen. Child responded dramatically and went into
Conventional cytogenetic analysis can identify
reciprocal chromosomal translocation t(15;17) in upto 90% of cases with
APL. The remaining 10% cases lacking t(15;17) stay associated with the
cryptic insertion of the PML/RARá fusion gene [4,5]. FISH analysis and
RT- PCR are the valuable tools to identify the PML/RARá hybrid
transcript in a cytogenetically negative APL patient. The routinely used
dual-colored break apart probes that are used in FISH are not sensitive
enough to hybridize with such small cryptic insertions and therefore do
not produce a signal as in our case. However, these small cryptic
insertions can be amplified and detected by RT-PCR. These RT-PCR
positive cases for hybrid PML/RARá transcript classify a new cytogenetic
subgroup of APL.
We suggest that RT-PCR should be performed at
baseline to detect this small subset of t(15;17) negative APL cases,
with cryptic or masked insertions.
1. Duan Y, Nie J, Zhang Z, Zhou L, Zhu F, Zhang H,
et al. A rare case with typical acute promyelocytic leukemia
morphology associated with isolated isochromosome 17q without RARá
rearrangement. Hematol Oncol Stem Cell Ther. 2013;6:42-5.
2. Huh J, Moon H, Chi H, Chung W. Acute promyelocytic
leukemia with i(17)(q10) on G-banding and PML/RARA rearrangement by
RT-PCR without evidence of PML/RARA rearrangement on FISH. Int J Lab
3. Choughule A, Polampalli S, Amre P, Shinde S,
Banavali S, Prabhash K, et al. Identification of PML/RARalpha
fusion gene transcripts that showed no t(15;17) with conventional
karyotyping and fluorescent in situ hybridization. Genet Mol Res.
4. Zaccaria A, Valenti A, Toschi M, Salvucci M,
Cipriani R, Ottaviani E, et al. Cryptic translocation of PML/RARA
on 17q. A rare event in acute promyelocytic leukemia. Cancer Genet
5. Kim M, Lim J, Kim Y, Han K, Lee DH, Chung NG, et al. The
genetic characterization of acute promyelocytic leukemia with cryptic
t(15;17) including a new recurrent additional cytogenetic abnormality i(17)(q10).