The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia

Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia.
Blood (Impact Factor: 10.45). 01/2008; 110(12):4073-6. DOI: 10.1182/blood-2007-06-095554
Source: PubMed


We report the molecular and cytogenetic characterization of a novel variant of acute promyelocytic leukemia (APL). The bone marrow showed 88% hypergranular promyelocytes, and the karyotype was 47,XY,+22 [5]/46,XY[30]. Fluorescence in situ hybridization (FISH) indicated disruption and deletion of the 5'-end of the RARA gene. Treatment with all-trans retinoic acid, idarubicin, and arsenic trioxide induced cytogenetic complete remission without morphologic evidence of residual leukemia. The diagnostic marrow was negative for PML-RARA transcripts by reverse transcription-polymerase chain reaction (RT-PCR), but an atypical product was observed. Sequencing showed partial homology to the PRKAR1A gene, encoding the regulatory subunit type I-alpha of cyclic adenosine monophosphate-dependent protein kinase. RT-PCR using specific primers for PRKAR1A and RARA amplified 2 transcript splice variants of a PRKAR1A-RARA fusion gene, and PRKAR1A and RARA FISH probes confirmed the fusion. This novel PRKAR1A-RARA gene rearrangement is the fifth variant APL in which the RARA partner gene has been identified and the second known rearrangement of PRKAR1A in a malignant disease. This trial was registered at with the Australian Clinical Trials Registry as number 12605000070639.

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    • "10.1016/j.blre.2014.09.013 rare partner genes (in addition to PML) which fuse to RARα have been previously described: NPM1, NUMA1, PLZF, PRKAR1A, FIP1L1, BCOR, STAT5B and a yet unidentified gene. These are represented by cytogenetic abnormalities t(5;17)(q35;q21), t(11;17)(q13;q21), t(11;17) (q23;q21), del(17)(q21;q24)/t(17;17)(q21;q24), t(4;17)(q12;q21), t(X;17)(p11;q12), der(17) and t(3;17)(p25;q21), respectively [15] [16] [17] [18] [19] [20] [21] [22]. "
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    ABSTRACT: Acute promyelocytic leukemia (APL) comprises approximately 5-10% of childhood acute myeloid leukemia (AML) cases in the US. While variation in this percentage among other populations was noted previously, global patterns of childhood APL have not been thoroughly characterized. In this comprehensive review of childhood APL, we examined its geographic pattern and the potential contribution of environmental factors to observed variation. In 142 studies (spanning > 60 countries) identified, variation was apparent—de novo APL represented from 2% (Switzerland) to > 50% (Nicaragua) of childhood AML in different geographic regions. Because a limited number of previous studies addressed specific environmental exposures that potentially underlie childhood APL development, we gathered 28 childhood cases of therapy-related APL, which exemplified associations between prior exposures to chemotherapeutic drugs/radiation and APL diagnosis. Future population-based studies examining childhood APL patterns and the potential association with specific environmental exposures and other risk factors are needed.
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    • "These represent leukemias with similar phenotype , but different genotype, and as such represent " experiments of nature " with which to test mechanistic hypotheses [25]. To date seven variant translocations have been characterized on a molecular basis: t(11;17)q(23;q21) [26] which fuses the PLZF transcriptional repressor to the same C-terminal sequences of RARA as are expressed in PML-RAR; t(5;17)(q35;q21) that joins nucleophosmin (NPM) to RARA [27]; t(11;17)(q13;q21) that fuses NUMA to RARA [28]; STAT5b-RARA [29] described in a patient with der 17; FIP1L1-RAR expressed in t(4;17)(q12;q21) [30]; fusion of RARA with the regulatory subunit of the cyclic adenosine monophosphate dependent protein kinase PRKAR1A on 17q24 [31]; and t(X;17)(p11;q12) which fuses BCOR to RARA [32]. We have focused our studies on t(5;17) NPM-RAR, which is the second most common of the variants, and which responds to the differentiating effect of ATRA [33], similar to t(15;17) APL. "
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    ABSTRACT: The t(5;17)(q35;q21) APL variant results in expression of a fusion protein linking the N-terminus of nucleophosmin (NPM) to the C-terminus of the retinoic acid receptor alpha (RAR). We have previously shown that NPM-RAR is capable of binding to DNA either as a homodimer or heterodimer with RXR. To determine the biological significance of NPM-RAR/RXR interaction, we developed two mutants of NPM-RAR that showed markedly diminished ability to bind RXR. U937 subclones expressing the NPM-RAR mutants showed significantly less inhibition of vitamin D3/TGFbeta-induced differentiation, compared with NPM-RAR. These results support the hypothesis that RXR interaction is necessary for NPM-RAR-mediated myeloid maturation arrest.
    Full-text · Article · Sep 2013 · Leukemia research
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    • "MPO was strongly positive, but expression of CD13, CD33, and CD11b was weak. The cells were negative for CD2, CD19, CD34, CD56, CD117, and HLA- DR (Catalano et al., 2007). "

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