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  • To overcome these resistance mechanisms in APL cells a numbe

    2019-05-22

    To overcome these resistance mechanisms in APL cells, a number of drugs have been tested. Tamibarotene is approximately 10 times more potent than ATRA as an in vitro inducer of differentiation, and is chemically more stable than ATRA [5]. Although the precise mechanism of the combination of tamibarotene and As2O3 in overcoming therapy resistance of APL silybin is not known, we suppose a certain synergistic effect of the drugs, as is observed in the combination of ATRA and As2O3[6,7]. Most importantly, our refractory patient, who had previously been treated with both tamibarotene and As2O3 monotherapies and could not enter hematological CR, achieved molecular CR by the combination therapy without severe adverse events, and has been in the molecular CR although the subsequent allogenic stem cell transplantation might significantly affect the clinical course. The combination of As2O3 and tamibarotene may be effective and tolerable for treating patients with refractory APL who have previously received various treatments including tamibarotene and As2O3, and have no treatment options.
    Author\'s contributions
    Conflict of interest
    Introduction Mixed phenotype acute leukemia (MPAL) is a rare hematological malignancy which is characterized by the generation of leukemic blasts with multilineage potential. Genetic analyses revealed that the BCR-ABL1 and KMT2A (MLL1) gene rearrangement in B-lymphoid/Myeloid MPAL are frequently detected, resulting in the formation of each subtype of MPAL. In addition, deletion 6 and 12p11.2 abnormalities have been observed in multiple cases [1,2]. On the other hand, the frequency and significance of PAX5 gene alteration located on 9p13.2, which have been reported in B-progenitor acute lymphoblastic leukemia (B-ALL), remains unknown in MPAL.
    Case report A 56-year-old male was referred to our hospital for evaluation of leukocytosis (29,800×109/L). A bone marrow examination showed a marked proliferation of blasts (88.3%) that were negative for myeloperoxidase (MPO) staining. These blasts were uniformly positive for CD19, CD10, TdT, CD34, MPO and HLA-DR based on the findings of flow cytometry (Fig. 1A), thus suggesting the presence of biphenotypic acute leukemia. A chromosomal analysis of the bone marrow cells revealed a complex karyotype including the derivative chromosome der(9)t(7;9)(q11.23;p13) (Fig. 1B). Transcripts of BCR-ABL1, ETV6-RUNX1, E2A-PBX1, MLL-AF4, MLL-AF6, MLL-AF9 and MLL-ENL were not detected. The patient was therefore diagnosed with MPAL of B-lymphoid/myeloid lineage (not otherwise specified).
    Result and discussion Three types of PAX5 fusion in B-ALL with t(7;9)(q11.2;p13) and der(9)t(7;9)(q11.2;p13), including PAX5-ELN, PAX5-AUTS2 and PAX5-POM12, have been reported thus far [3]. In order to analyze the alteration of the PAX5 gene in the present case, we utilized the 3′ RACE-PCR method. We detected an aberrant PAX5 transcript, including exons 1A to 5 and the contiguous intron 5/6 sequence. The presumably truncated PAX5 protein was composed of 256 amino acids. It preserved the paired domain for DNA binding at the N-terminus and acquired an aberrant C-terminus, instead of the transactivation and inhibitory domains for transcription regulation. The expression of this transcript and wild-type transcript (derived from a wild-type allele) in the leukemic blasts was confirmed by reverse transcription (RT)-PCR (Fig. 2). The addition of the intron 5/6 sequence at the 3′ end was supposed to be generated by chromosomal translocation without the fusion partner gene at 9q13; The PAX gene was simply broken at intron 5/6 without the supply of a splice acceptor site at the 3′ end of the intron, resulting in the in-frame transcription of the unremoved intron sequence. An identical truncated transcript was also detected in 3 B-ALL cases including a case with dic(9;16)(p13;q11), but not der(9)t(7;9)(q11.2;p13) [4], suggesting that this genetic alteration can be generated by genomic instability that is not related to a specific rearrangement of PAX5.