Cryptic recurrent ACIN1‐NUTM1 fusions in non‐KMT2A‐rearranged infant acute lymphoblastic leukemia

Abstract

Infant acute lymphoblastic leukemias (ALL) are rare hematological malignancies occurring in children younger than 1 year of age, most frequently associated with KMT2A rearrangements (KMT2A‐r). The smaller subset without KMT2A‐r, which represents 20% of infant ALL cases, is poorly characterized. Here we report two cases of chemotherapy‐sensitive non‐KMT2A‐r infant ALL. Transcriptome analyses revealed identical ACIN1‐NUTM1 gene fusions in both cases, derived from cryptic chromosomal rearrangements undetected by standard cytogenetic approaches. Two isoforms of the gene fusion, joining exons 3 or 4 of ACIN1 to exon 3 of NUTM1, were identified. Both fusion transcripts contained the functional DNA‐binding SAP (SAF‐A/B, Acinus, and PIAS) domain of ACIN1 and most of NUTM1. The detection of the ACIN1‐NUTM1 fusion by RT‐PCR allowed the molecular monitoring of minimal residual disease in a clinical setting. Based on publicly available genomic datasets and literature review, we predict that NUTM1 gene fusions are recurrent events in infant ALL. As such, we propose two clinically relevant assays to screen for NUTM1 rearrangements in bone marrow cells, independent of the fusion partner: NUMT1 immunohistochemistry and NUTM1 RNA expression. In sum, our study identifies ACIN1‐NUTM1 as a recurrent and possibly cryptic fusion in non‐KMT2A‐r infant ALL, provides clinical tools to screen for NUTM1‐rearranged leukemia and contributes to the refinement of this new subgroup.

Transcriptome Profiling Reveals B-Lineage Cells Contribute to the Poor Prognosis and Metastasis of Clear Cell Renal Cell Carcinoma

“…Based on the above method, 5 genes, including STX16, CLASRP, ATIC, ACIN1 and SEMA4B, were identified to be relevant to poor prognosis of ccRCC patients. It has been reported that high serum levels of STX16 was associated with esophageal squamous cell carcinoma (24), CLASRP was associated with head and neck cancers (25), ATIC promoted the development of hepatocellular carcinoma (26) and hypermethylated ACIN1 was observed in lung adenocarcinoma and acute lymphoblastic leukemia (27,28). This correlates with the observations from long-term follow-up studies that cancer patients carrying these up-regulated genes exhibited poor prognosis (Figure 3C).…”

Emerging entities in NUTM1‐rearranged neoplasms

“…Interestingly, BRD9, while not categorized as a BET protein, contains a single bromodomain and binds the lysine residues of acetylated histones. ACIN1‐NUTM1 fusions have now also been reported on several more occasions in infant and pediatric ALLs . Other NUTM1 fusion partners reported in ALL are IKZF1 , ZNF618 , AFF1 , SLC12A6 , CUX1 , and BPTF …”

“…ACIN1-NUTM1 fusions have now also been reported on several more occasions in infant and pediatric ALLs. 72,[76][77][78][79] Other NUTM1 fusion partners reported in ALL are IKZF1, 76 With a single exception, all of these NUTM1 fusion partners are predicted to associate directly with DNA and/or participate in chromatin remodeling. The exception, solute carrier family 12 member 6 (SLC12A6), also known as K-Cl cotransporter C (KCC3), is a member of the K-Cl cotransporter family.…”

Prevalence of NUT carcinoma in head and neck: Analysis of 362 cases with literature review

“…Recently, NUTM1 is becoming less specific for NC, and many novel fusion partner genes were identified in sarcoma and hematologic malignancy. 39,[41][42][43][44][45][46] Nineteen cases of NUTM1-associated sarcoma were summarized in the Table 5 45 The prognosis of NUTM1-associated sarcoma is generally poor, except one ZNF532, one MXD1, two MGA, and one CIC fusion partner gene cases. In IHC, most NC cells showed positivity for squamous cell markers, p63 and p40, and about half of cases showed immunoreactivity for CD34.…”