NUP98-HOXA9 bearing therapy-related myeloid neoplasm involves myeloid-committed cell and induces HOXA5, EVI1, FLT3,...

Chromosomal rearrangements involving NUP98 gene have been associated with human leukemias such as de novo AML, therapy-related AML (t-AML), myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML). Genetic fusion NUP98-HOXA9, caused by t(7;11)(p15;p15), is a recurrent cytogenetic alteration in de novo acute myeloid leukemia (AML) usually found in young Asian patients and its description in therapy-related myeloid neoplasms (t-MN) is rare. Only one Asian case with molecular demonstration of the NUP98-HOXA9 fusion has been reported in therapy-related leukemia. NUP98-HOXA9 leukemogenic mechanism is derived from the transcription factor activity of the chimeric protein, which enhances the expression of genes related to cellular differentiation arrest and proliferation.

We studied a Caucasian woman with a therapy-related acute myeloid leukemia after Ewing's sarcoma. Molecular demonstration of the genetic fusion NUP98-HOXA9 was performed by RT-PCR, and gene expression was analyzed by real-time PCR, including four AML patients with MLL rearrangements for comparative analysis. Cytologic and flow cytometric analysis was also carried out.

After cytologic and flow cytometric analysis diagnostics was therapy-related myeloid neoplasm (t-MN). The major component of blasts in the acute leukemia was with neutrophilic differentiation, but 13% erythroid lineage blasts were also found. Cytogenetic and FISH analysis revealed t(7;11)(p15;p15) and NUP98-HOXA9 fusion gene was demonstrated. Gene expression analysis showed upregulation of EVI1 and MEIS1 in the index patient, both of them previously related to a worst outcome.

In this work, we include a detailed molecular, clinical, cytological, and cytometric study of the second t-AML bearing NUP98-HOXA9 genetic fusion.