TMEM91::TAL1 Fusion gene in a middle-aged female with rapid MDS to secondary AML progression: a case report

TMEM91::TAL1 fusion has been identified in glioblastoma but has never been documented in hematologic malignancies. We document the first presentation of the TMEM91::TAL1 fusion in a myelodysplastic syndrome (MDS) with rapid transition into secondary acute myeloid leukemia (sAML).

A middle-aged female presented to the hematology clinic complaining primarily of fatigue and a workup revealing pancytopenia. Bone marrow (BM) biopsy demonstrated 8% blasts with myelodysplastic changes and secondary myelofibrosis. RNA sequencing detected the TMEM91::TAL1 fusion at 1.79% in the presence of normal cytogenetics and a minimal inhibitory DNMT3A mutation (1.3%). Despite multiple cycles of azacitidine, within one month, the patient had transitioned into sAML with blasts increased to 55% with heterogeneity in the sample, and TMEM91::TAL1 expression increased to 2.83%. The patient underwent haploidentical stem cell transplantation with complete remission and no evidence of TMEM91::TAL1 fusion.

The TMEM91::TAL1 fusion (resulting from a breakpoint at exon 3 of TMEM91 and exon 5 of TAL1) was detected by RNA-seq while not detected by whole genome sequencing. The expression of TMEM91::TAL1 fusion increased with the progression from MDS to sAML and was eliminated after HSCT. This case illustrates the value of comprehensive molecular profiling, including RNA-seq, in cases of rapidly progressive MDS that cannot be diagnosed through standard molecular diagnostics. The temporal relationship between expression of the fusions and disease progression warrants additional studies of TMEM91::TAL1 in myeloid malignancies.