NUTM1 is a recurrent fusion gene partner in B-cell precursor acute lymphoblastic leukemia associated with increased expression of genes on chromosome band 10p12.31-12.2

Abstract

NUTM1 is a recurrent fusion gene partner in B-cell precursor acute lymphoblastic leukemia associated with increased expression of genes on chromosome band 10p12.31-12.2 For 20-25% of patients with pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), the driving cytogenetic aberration is unknown. Identification of the primary lesion could provide better risk stratification and even identify possible treatment options. We therefore aimed to find novel recurrent genetic aberrations in BCP-ALL cases. We identified an in-frame SLC12A6-NUTM1 fusion, resulting in expression of 3' exons of NUTM1, and six additional NUTM1-rearranged fusion cases. These NUTM1-rearranged cases were associated with high expression of a cluster of genes on chromosome band 10p12.31-12.2, including the BMI1 gene. Our data point to NUTM1 fusions as a new entity of BCP-ALL negative for known genetic abnormalities. Pediatric BCP-ALL consists of many cytogenetic subtypes, each with a different prognosis. 1 ETV6-RUNX1 fusions, high hyperdiploid, and TCF3-PBX1 fusions have a favorable prognosis, while BCR-ABL1 fusions and KMT2A/MLL-rearrangements have a poor prognosis.

Emerging entities in NUTM1‐rearranged neoplasms

“…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 . Our analysis of the SLC12A6‐NUTM1 fusion described by Hormann et al reveals that it is in‐frame and that the fusion protein is expressed. The predicted protein comprises only a short N‐terminal region of SLC12A6 (32‐91 amino acids depending on the transcript) that contains no known functional domain.…”

“…Since p300 preferentially binds a risk allele of BMI1 associated with an increased likelihood for BCP‐ALL the authors speculate that NUTM1 fusion proteins contribute to leukemogenesis by stimulating p300 which leads to the upregulation of BMI1 and other 10p12.31 genes. In addition, upregulated in ACIN1‐ and CUX1‐NUTM1 ALLs was the HOXA4 gene cluster on chromosome 7p . The detection of upregulated HOXA4 genes in ACIN1‐ and CUX1‐ , but not SLC12A6‐ or IKZF1‐NUTM1 ALLs has been documented twice, providing further evidence that specific NUTM1 fusion partners drive oncogenesis via distinct, though likely related, mechanisms.…”

“…In addition, upregulated in ACIN1‐ and CUX1‐NUTM1 ALLs was the HOXA4 gene cluster on chromosome 7p . The detection of upregulated HOXA4 genes in ACIN1‐ and CUX1‐ , but not SLC12A6‐ or IKZF1‐NUTM1 ALLs has been documented twice, providing further evidence that specific NUTM1 fusion partners drive oncogenesis via distinct, though likely related, mechanisms.…”

“…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 …”

“…Almost no details are known regarding the oncogenic function of the other ALL‐associated NUTM1 fusions. Gene expression studies comparing NUTM1‐expressing vs nonexpressing pediatric B‐other ALL cases have found upregulation of the genes in cytoband 10p12.31, including the oncogene BMI1 . Since p300 preferentially binds a risk allele of BMI1 associated with an increased likelihood for BCP‐ALL the authors speculate that NUTM1 fusion proteins contribute to leukemogenesis by stimulating p300 which leads to the upregulation of BMI1 and other 10p12.31 genes.…”