Oncogenomic profiling in infant–toddler T‐ALL identifies NKX2 family genes as drivers linked to favorable outcomes

T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive hematological malignancy primarily affecting adolescents and young adults and is scarce in infants and toddlers under age 3. Unlike B-ALL, T-ALL in this young population remains poorly characterized due to limited data and lacks evidence-based guidelines to help clinicians determine the optimal treatment approach. In this study, we conducted a comprehensive genetic analysis of infant/toddler T-ALL cases from a French national cohort, utilizing high-throughput targeted sequencing, optical genome mapping, and RNA sequencing. Genetic analysis revealed the absence of <i>TLX1/3</i> dysregulation. Instead, we identified a significant prevalence of <i>NKX2</i> rearrangements (<i>n</i> = 9, 33%), co-occurring with <i>MYB</i> alterations (<i>n</i> = 5/9) or chromothripsis-like events (<i>n</i> = 3/9). Additional findings included <i>TAL1/-like</i> anomalies (30%), <i>STAG2::LMO2</i> (15%), <i>ETS</i> rearrangements (15%), and rarely, <i>KMT2A</i> rearrangements (7%). Comparative analyses with 245 patients aged 3-18 years, enrolled in the pediatric FRALLE2000T French protocol, underscored the distinct clinical and genetic profiles of infants/toddlers. Despite presenting with higher rates of hyperleukocytosis and slower responses to treatment, they demonstrated comparable survival outcomes to older pediatric patients, with a 5-year overall survival (OS) rate of 75.4% (95% confidence interval [CI]: 60.0%-94.8%) versus 75.2% (95% CI: 69.8%-81.1%), <i>p</i> = 0.86. Notably, alterations in <i>NKX2</i>, <i>KMT2A</i>, and <i>STAG2::LMO2</i> delineated oncogenic subgroups exhibiting a remarkable 100% OS rate, while patients with <i>TAL1</i> or <i>ETS</i> dysregulation experienced less favorable outcomes. This was further supported by analyses of data from the COG AALL0434 trial, enhancing our understanding of T-ALL in infants/toddlers. Large-scale collaborative studies remain essential to confirm these findings and refine treatment strategies.

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Journal
HemaSphere
Published
2025-05-01
DOI
https://doi.org/10.1002/hem3.70154
Citations
1
Primary Topic
Acute Lymphoblastic Leukemia research
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article
Field-Weighted Citation Impact
1.88

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article

Oncogenomic profiling in infant–toddler T‐ALL identifies NKX2 family genes as drivers linked to favorable outcomes

Isabelle Pellier, Benoît Brethon, André Baruchel, Christophe Gillet et al.
1 citations
HemaSphere
Acute Lymphoblastic Leukemia research
1.88
article

Oncogenomic profiling in infant–toddler T‐ALL identifies NKX2 family genes as drivers linked to favorable outcomes

Isabelle Pellier, Benoît Brethon, André Baruchel, Christophe Gillet, Nathalie Garnier, Marion Lubnau, Aurore Touzart, Thomas Mercher, Lucien Courtois, Guillaume Charbonnier, Mélanie Féroul, Damien Bodet, Nathalie Grardel, Manon Delafoy, Antoine Pinton, Mathieu Simonin, Pierre‐Simon Rohrlich, Charlotte Smith, Arnaud Petit, Paul Saultier, Vahid Asnafi, Sandrine Thouvenin, Margaux Wiber, Estelle Balducci, Ludovic Lhermitte, Elizabeth Macintyre, Agata Cieślak, Sylvain Latour, Cédric Pastoret, Isabelle Arnoux, Marianne Courgeon
article en
1 citations

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive hematological malignancy primarily affecting adolescents and young adults and is scarce in infants and toddlers under age 3. Unlike B-ALL, T-ALL in this young population remains poorly characterized due to limited data and lacks evidence-based guidelines to help clinicians determine the optimal treatment approach. In this study, we conducted a comprehensive genetic analysis of infant/toddler T-ALL cases from a French national cohort, utilizing high-throughput targeted sequencing, optical genome mapping, and RNA sequencing. Genetic analysis revealed the absence of <i>TLX1/3</i> dysregulation. Instead, we identified a significant prevalence of <i>NKX2</i> rearrangements (<i>n</i> = 9, 33%), co-occurring with <i>MYB</i> alterations (<i>n</i> = 5/9) or chromothripsis-like events (<i>n</i> = 3/9). Additional findings included <i>TAL1/-like</i> anomalies (30%), <i>STAG2::LMO2</i> (15%), <i>ETS</i> rearrangements (15%), and rarely, <i>KMT2A</i> rearrangements (7%). Comparative analyses with 245 patients aged 3-18 years, enrolled in the pediatric FRALLE2000T French protocol, underscored the distinct clinical and genetic profiles of infants/toddlers. Despite presenting with higher rates of hyperleukocytosis and slower responses to treatment, they demonstrated comparable survival outcomes to older pediatric patients, with a 5-year overall survival (OS) rate of 75.4% (95% confidence interval [CI]: 60.0%-94.8%) versus 75.2% (95% CI: 69.8%-81.1%), <i>p</i> = 0.86. Notably, alterations in <i>NKX2</i>, <i>KMT2A</i>, and <i>STAG2::LMO2</i> delineated oncogenic subgroups exhibiting a remarkable 100% OS rate, while patients with <i>TAL1</i> or <i>ETS</i> dysregulation experienced less favorable outcomes. This was further supported by analyses of data from the COG AALL0434 trial, enhancing our understanding of T-ALL in infants/toddlers. Large-scale collaborative studies remain essential to confirm these findings and refine treatment strategies.

HemaSphereVol. 9(5)
Inserm (FR), Délégation Paris 7 (FR), Université Paris Cité (FR), Aix-Marseille Université (FR), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), Centre Hospitalier Universitaire de Lille (FR), Centre Hospitalier Universitaire de Nice (FR), Sorbonne Université (FR), Institut Necker Enfants Malades (FR), Hôpital Armand-Trousseau (FR), Institut d’Hématologie et d’Oncologie Pédiatrique (FR), Assistance Publique – Hôpitaux de Paris (FR), Centre Hospitalier Régional et Universitaire de Nancy (FR), Hospices Civils de Lyon (FR), Centre Hospitalier Universitaire d'Angers (FR), Centre Hospitalier Universitaire de Rennes (FR), Centre Hospitalier Universitaire de Saint-Étienne (FR), Institut des Maladies Génétiques Imagine (FR), Université de Rennes (FR), University of Birmingham (GB), Université de Caen Normandie (FR)
Société Française de lutte contre les Cancers et les leucémies de l'Enfant et de l'Adolescent, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Ligue Contre le Cancer, Institut National Du Cancer
Good health and well-being
Openalex Percentile: Top 15%
Acute Lymphoblastic Leukemia research
1.88
DOIOpen Access PDFOpenAlex
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