PAN3–PSMA2 fusion resulting from a novel t(7;13)(p14;q12) chromosome translocation in a myelodysplastic syndrome that evolved into acute myeloid leukemia

Abstract

BackgroundAcquired primary chromosomal changes in cancer are sometimes found as sole karyotypic abnormalities. They are specifically associated with particular types of neoplasia, essential in establishing the neoplasm, and they often lead to the generation of chimeric genes of pathogenetic, diagnostic, and prognostic importance. Thus, the report of new primary cancer-specific chromosomal aberrations is not only of scientific but also potentially of clinical interest, as is the detection of their gene-level consequences.Case presentationRNA-sequencing was performed on a bone marrow sample from a patient with myelodysplastic syndrome (MDS). The karyotype was 46,XX,t(7;13)(p14;q12)[2]/46,XX[23]. The MDS later evolved into acute myeloid leukemia (AML) at which point the bone marrow cells also contained additional, secondary aberrations. The 7;13-translocation resulted in fusion of the gene PAN3 from 13q12 with PSMA2 from 7p14 to generate an out-of-frame PAN3–PSMA2 fusion transcript whose presence was verified by RT-PCR together with Sanger sequencing. Interphase fluorescence in situ hybridization analysis confirmed the existence of the chimeric gene.ConclusionsThe novel t(7;13)(p14;q12)/PAN3–PSMA2 in the neoplastic bone marrow cells could affect two key protein complex: (a) the PAN2/PAN3 complex (PAN3 rearrangement) which is responsible for deadenylation, the process of removing the poly(A) tail from RNA, and (b) the proteasome (PSMA2 rearrangement) which is responsible for degradation of intracellular proteins. The patient showed a favorable response to decitabine after treatment with 5-azacitidine and conventional intensive chemotherapy had failed. Whether this might represent a consistent feature of MDS/AML with this particular gene fusion, remains unknown.

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…Three recurrent gene mutations (RUNX1, ASXL1, and TP53) have been added in the risk stratification of the ELN-2017 recommendations for AML [2]. Recently, more novel fusion genes, such as GTF2I-PDGFRB and IKZF1-TYW1 fusion genes, and PAN2/PAN3 complex, have reported and may be clinically important [120,121]. As the new technology advances, more recurrent gene mutations will be explored and used for AML risk stratification and treatment guidelines.…”

CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p–XIAP axis

“…A recent study has reported that the gene PAN3 is considered a candidate gene located in amplified chromosome regions in AML patients with a complex karyotype [21]. In a myelodysplastic syndrome patient that evolved into AML, a fusion of PAN3 with the gene PSMA2 was formed from a chromosome translocation [29], suggesting a potential association between the PAN3 gene and AML development. As further evidence addressing the role of PAN3 in AML, our in vitro experiments found that downregulation of circ-PAN3 by siRNA considerably increased the sensitivity of drug-resistant THP-1/ADM cells to ADM; however, after histopathological examination, a significantly higher expression level of circPAN3 was observed in the BM samples from refractory/recurrent AML patients.…”

Neoplasia-associated Chromosome Translocations Resulting in Gene Truncation

“…Many chromosome translocations resulting in truncated or fused genes leading to out-of-frame transcripts have been reported only once. These events might turn out to be recurrent if and when the second case, and then the third et cetera, is reported, as for the leukemias with t(8;19)/KAT6A::LEUTX described between 1988 and 1995 and t(11;20)/ZMYND8::RELA between 2013 and 2018 (33,37,38,40,53,67,(89)(90)(91)(92)(93)(94)(118)(119)(120)(121). In 1985, De Braekeleer and coworkers reported an acute lymphoblastic leukemia carrying a t(10;19)(q26;q13) as the sole cytogenetic change (122).…”

“…The reality of these gene fusions is then confirmed (or ruled out) using yet other methods such as FISH, PCR, and Sanger sequencing analyses (33,45,77,(84)(85)(86)(87)(88). This approach also has the advantage of not overlooking "non-canonical" fusion genes or rearranged genes that lead to truncated proteins (42,51,58,(89)(90)(91)(92)(93)(94).…”