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    • The PAX gene encodes a transcriptional

    2019-05-17

    The PAX5 gene encodes a transcriptional factor, which is specifically expressed at the early stages of B-cell differentiation and it is required for B-cell development. Its dysregulation is involved in the leukemogenesis of B-ALL. The PAX5 gene rearrangements account for approximately 2.5% of pediatric B-ALL cases [5]. A genome-wide analysis revealed that one-third of pediatric B-ALL cases had somatic mutations in PAX5, which resulted in the generation of a hypomorphic allele of the PAX5 gene [6]. Chemical and retroviral mutagenesis significantly increases the penetrance of B-ALL in mice with a heterozygous loss-of-function mutation of PAX5[7], suggesting that the reduced expression and dysregulation of PAX5 function are closely related to the development of B-ALL. However, the PAX5 function in bi-phenotypic B-lymphoid/myeloid order Cyclosporin A remains obscure; one study showed that ectopic PAX5 expression was required for their maintenance [8]. Another demonstrated that low-level PAX5 expression was required for MPAL development [9]. To the best of the authors’ knowledge, there are no other case reports of PAX5 gene or 9p13.2 abnormalities in MPAL patients. The truncated PAX5 that was observed in the present study behaves as a competitive inhibitor of wild-type PAX5 transcriptional activity [6], suggesting that the truncated PAX5 may also contribute to the development of MPAL by inhibiting the function of wild-type PAX5.
    Authors\' contributions
    Competing interests
    Case description A 41-year-old woman prompted a visit to an optometrist due to blurred vision in June 2013, and was diagnosed to have retinal hemorrhage. Complete blood count revealed marked leukocytosis (326K/µL), neutrophilia (25%, 64.6K/µL) with a prominent myelocyte peak (27.5% myelocytes), basophilia (4.0%, 12.9K/µL), and mild normocytic anemia (Hemoglobin 10.4g/dl). Bone marrow study revealed hyperplastic myeloid series (myeloid/erythroid ratio of 8.1/1) with only 1.2% blasts. Further both karyotype and FISH analysis revealed presence of Philadelphia chromosome in nearly all cells (Fig. 1A and B) Based on these findings patient was diagnosed with Chronic myeloid leukemia (CML), chronic phase. She was started on Imatinib 400mg daily and hydroxyurea. Despite achieving hematological remission three months after diagnosis, patient continued to have persistent cytogenetic disease as detected on follow up FISH assays with 32% cells showing t (9; 22). In June 2014, patient was switched to Nilotinib, as she appeared to have Imatinib resistant disease, although molecular testing for ABL kinase mutational analysis was negative. In July 2015 repeat blood work was done as patient complained of progressive fatigue and menorrhagia. CBC done at that time revealed a normal white cell count of 9.1K/µL with 17.5% circulating blasts, (Fig. 1C) and hemoglobin of 7.5g/dL. Bone marrow aspiration and biopsy was performed and the specimen was also submitted for flow cytometry and cytogenetic analysis. Prominent erythroid hyperplasia was noted on the bone marrow aspirate smears with 69.5% erythroid precursors, several of which showed dysplastic features (Fig. 1D–F). Although only 9% blasts were counted on the bone marrow differential count, flow cytometry revealed 14% cells in the blast gate (Fig. 1G) mostly expressing myeloid markers CD117, CD33, stem cell marker CD34 and with partial aberrant expression of lymphoid marker CD7. Bone marrow biopsy sections revealed marked architectural disarray with prominent erythroid hyperplasia (Fig. 1H) and normal number of megakaryocytes several of which were small and unilobed. Although no solid sheets of blasts were seen, CD34 highlighted scattered blasts throughout the biopsy section with a variable distribution estimated at approximately 10–15% (Fig. 1I). Both karyotype and FISH analysis revealed presence of Philadelphia chromosome. Additionally monosomy 7 was detected in 82% of the cells (Fig. 1J and K) and chromosome 3 anomaly was also noted. Based on the presence of marked erythroid hyperplasia (69.5%) and 9% bone marrow blasts the diagnostic criteria for acute erythroid/myeloid leukemia were met and a diagnosis of blast transformation of underlying CML to acute erythroid/myeloid leukemia was made.