PMC9626966_01
A brief summary of the medical history and comprehensive molecular-genetic analysis. (A) Patient timeline of key clinical events and laboratory test results. (B) The patient was born with four Fanconi anemia (FA) gene mutations and germline predisposition to cancers. She developed ovarian cancer, and then the altered FA pathway plus exposure to cytotoxic drugs promoted the emergence of acquired somatic mutations and the NUP98-HOXC11 fusion, all of which contributed to the development of secondary t-CMML. (C) Potential biological mechanisms contributing to the pathogenesis of t-CMML.
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Morphology, karyotyping and molecular characterization of the NUP98-HOXC11 fusion. (A) A diagnostic bone marrow (BM) aspirate smear revealed dysplasia in granulocytic and megakaryocytic cell lineages and enriched naive monocytes (Wright stained, x 1000). (B) Karyotyping performed on the diagnostic BM revealed 46, XX, t(11;12)(p15;q13) [8]. (C) Upper panel, Sanger sequencing was performed to verify the NUP98-HOXC11 fusion transcript containing exon 12 of NUP98 fused to exon 2 of HOXC11. Lower panel, a schematic diagram showing the NUP98-HOXC11 in-frame fusion and phenylalanine-glycine/glycine-leucine-phenylalanine-glycine (FG/GLFG) repeats and Gle2-binding sequence (GLEBS) domain in the amino-terminal portion of NUP98 retained in the fusion protein.
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Morphological examination of a bone marrow (BM) aspirate revealed dysplasia in granulocytic and megakaryocytic cell lineages and an increased naive monocyte percentage (approximately 10%) ( Figure 2A ). CD34, CD117, CD38, CD9dim, CD13dim, and CD33 and that naive monocytes with a percentage of 8.4% in total nucleated cells expressed the markers CD64bri, CD11cbri, CD15dim, and CD14neg ( Figure S2 ;  Supplemental Material ). Cytogenetic analysis revealed an abnormal karyotype of "46, XX, t (11; 12)(p15; q13) [8]" ( Figure 2B ). To confirm the NUP98-HOXC11 fusion, reverse transcription polymerase chain reaction (RT-PCR) was performed with a pair of primers, forward (at NUP98 exon 12): 5'-TCTTGGTACAGGAGCCTTTGG-3', and reverse (at HOXC11 exon 2): 5'-GTTCCCGGATCTGGAATTTCG-3', and then the amplified PCR products were purified to perform Sanger sequencing to verify the above finding ( Figure 2C ).