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Fusion of FIP1L1 and RARA as a result of a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia

Leukemia volume 21, pages 1104–1108 (2007)Cite this article

We report on reciprocal FIP1L1/RARA fusion transcripts resulting from a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia (JMML). JMML is a pediatric myeloproliferative disease (MPD), characterized by proliferation of granulocytic and monocytic lineages with in vitro hypersensitivity to granulocyte/macrophage colony stimulating factors (GM-CSF). Mutations in N/K-RAS (20–30%), PTPN11 (35%) and NF1 (10%) have been identified, indicating deregulation of the RAS/MAPK pathway in JMML. 17q12 RARA was demonstrated to be involved in t(15;17)(q22;q21), resulting in a PML/RARA fusion transcript. PML/RARA t(15;17) is the hallmark of acute promyelocytic leukemia (APL), characterized by a differentiation arrest of abnormal promyelocytes.1 Variant rearrangements involving 17q21 RARA in APL and APL-like (APL-L) disease are PLZF/RARA t(11;17)(q23;q21), NPM1/RARA t(5;17)(q35;q21), NUMA/RARA t(11;17)(q13;q21), STAT5b/RARA der(17) and t(3;17)(p25;q21).1, 2 All known RARA fusion protein partners have the ability to self-associate, which is critical for oncogenesis.3 In chronic eosinophilic leukemia (CEL) an FIP1L1/PDGFRA fusion gene has been identified owing to a chromosome 4q12 interstitial deletion.4 FIP1L1 is an integral subunit of cleavage and polyadenylation specificity factor (CPSF) and interacts with poly(A)polymerase (PAP) to stimulate polyadenylation.5

In the fall of 2005, we decided to further characterize the case from March 1996, by FISH and reverse transcription-polymerase chain reaction (RT-PCR) analyses, for diagnostically relevant gene rearrangements on cryopreserved bone marrow and peripheral blood. No BCR/ABL1, PML/RARA, RUNX1/RUNX1T1, CBFB/MYH11 or 11q23 MLL gene rearrangements were detected. No mutation either in exons 3 and 14 of PTPN11, or in exons 1 and 2 of K- and N-RAS was demonstrated by direct sequencing after amplification.

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Acknowledgements

We thank Kees Geurts, Daniel Olde Weghuis and Henny de France for initial cytogenetic analysis; Tiny Tammer, Eric Borst, Nicole de Waal and Wil van Dijk for excellent technical assistance. We acknowledge the patient material provided by Dr Elisabeth van Wering, Dutch Childhood Oncology Group, The Hague, The Netherlands. We thank Dr Miranda Buitenhuis and Professor Paul Coffer for communicating unpublished results.

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  1. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    A Buijs

  2. Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands

    M Bruin

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Buijs, A., Bruin, M. Fusion of FIP1L1 and RARA as a result of a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia. Leukemia 21, 1104–1108 (2007). https://doi.org/10.1038/sj.leu.2404596

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