Favorable outcome of NUTM1-rearranged infant and pediatric B cell precursor acute lymphoblastic leukemia in a collaborative international study

Boer, Judith M.; Valsecchi, Maria Grazia; Hormann, Femke M.; Antić, Željko; Žaliová, Markéta; Schwab, Claire; Cazzaniga, Giovanni; Arfeuille, Chloé; Cavé, Hélène; Attarbaschi, Andishe; Strehl, Sabine; Escherich, Gabriele; Imamura, Toshihiko; Ohki, Kentaro; Grüber, Tanja A.; Sutton, Rosemary; Pastorczak, Agata; Lammens, Tim; Lambert, Frédéric; Li, Chi Kong; Pau, Enrique Carrillo de Santa; Hoffmann, Steve; Möricke, Anja; Harrison, Christine J.; Boer, Monique L. Den; Lorenzo, Paola De; Stam, Ronald W.; Bergmann, Anke; Pieters, Rob

doi:10.1038/s41375-021-01333-y

Cited by 44 publications

(51 citation statements)

References 15 publications

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“…Furthermore, we showed in a small cohort of patients that an immature (CD10-negative) pro-B immunophenotype predicted a worse outcome in infants with KMT2A-g ALL [10]. More recently, although in a limited series of cases, a poor prognostic value was shown for PAX5 fusions and a good outcome was associated with NUTM1 gene fusions, both correlated with MRD response [11,12]. Overall, the relevance of MRD is still unknown in infants with KMT2A-g ALL.…”

Section: Introductionmentioning

confidence: 77%

Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

Stutterheim

Lorenzo

Sluin

et al. 2022

European Journal of Cancer

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Section: Introductionmentioning

confidence: 77%

Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

Stutterheim

Lorenzo

Sluin

et al. 2022

European Journal of Cancer

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“…NUTM1 (nuclear protein in testis midline carcinoma family 1) rearrangements (<2% of childhood B-ALL and mostly infant without KMT2A-rearrangements) [7,13,88,[98][99][100] are characterized by fusion of NUTM1 to different partners, including transcription factors and epigenetic regulators (e.g., ACIN1, AFF1, ATAD5, BRD9, CHD4, CUX1, IKZF1, RUNX1, SLC12A6, and ZNF618), that drive aberrant NUTM1 expression [7,13]. In all fusions, the NUT domain is retained, and this is hypothesized to lead to global changes in chromatin acetylation [101] and to sensitivity to histone deacetylase inhibitors or bromodomain inhibitors in case of fusions with BRD9.…”

Section: Dux4 Mef2d Znf384 and Nutm1 Gene Fusionsmentioning

confidence: 99%

“…In all fusions, the NUT domain is retained, and this is hypothesized to lead to global changes in chromatin acetylation [101] and to sensitivity to histone deacetylase inhibitors or bromodomain inhibitors in case of fusions with BRD9. NUTM1 rearrangements confer an excellent prognosis to current therapeutic approaches [82,83,98]. Since not all NUTM1 fusions are detectable by karyotyping either break-apart FISH or, preferably, WTS are the best approaches for diagnosis.…”

Section: Dux4 Mef2d Znf384 and Nutm1 Gene Fusionsmentioning

confidence: 99%

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

Iacobucci

Kimura

Mullighan

2021

JCM

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Acute lymphoblastic leukemia (ALL) is the most successful paradigm of how risk-adapted therapy and detailed understanding of the genetic alterations driving leukemogenesis and therapeutic response may dramatically improve treatment outcomes, with cure rates now exceeding 90% in children. However, ALL still represents a leading cause of cancer-related death in the young, and the outcome for older adolescents and young adults with ALL remains poor. In the past decade, next generation sequencing has enabled critical advances in our understanding of leukemogenesis. These include the identification of risk-associated ALL subtypes (e.g., those with rearrangements of MEF2D, DUX4, NUTM1, ZNF384 and BCL11B; the PAX5 P80R and IKZF1 N159Y mutations; and genomic phenocopies such as Ph-like ALL) and the genomic basis of disease evolution. These advances have been complemented by the development of novel therapeutic approaches, including those that are of mutation-specific, such as tyrosine kinase inhibitors, and those that are mutation-agnostic, including antibody and cellular immunotherapies, and protein degradation strategies such as proteolysis-targeting chimeras. Herein, we review the genetic taxonomy of ALL with a focus on clinical implications and the implementation of genomic diagnostic approaches.

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“…Two patients have received HDAC inhibitor treatment. A pediatric patient receiving the HDAC inhibitor vorinostat showed a marked decrease in tumor avidity for 18 F-fluorodeoxyglucose observed by positron emission tomography [17], an early sign of tumor response. Another patient showed disease progression after the first dose of Romidepsin (a different HDAC inhibitor) [99].…”

Section: Targeted Therapymentioning

confidence: 99%

NUTM1-Rearranged Neoplasms—A Heterogeneous Group of Primitive Tumors with Expanding Spectrum of Histology and Molecular Alterations—An Updated Review

et al. 2021

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Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update on NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects.

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Favorable outcome of NUTM1-rearranged infant and pediatric B cell precursor acute lymphoblastic leukemia in a collaborative international study

Cited by 44 publications

References 15 publications

Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

NUTM1-Rearranged Neoplasms—A Heterogeneous Group of Primitive Tumors with Expanding Spectrum of Histology and Molecular Alterations—An Updated Review

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