RESUMEN

Chromosomal rearrangements involving the KMT2A gene occur frequently in acute lymphoblastic leukaemia (ALL). KMT2A-rearranged ALL (KMT2Ar ALL) has poor long-term survival rates and is the most common ALL subtype in infants less than 1 year of age. KMT2Ar ALL frequently occurs with additional chromosomal abnormalities including disruption of the IKZF1 gene, usually by exon deletion. Typically, KMT2Ar ALL in infants is accompanied by a limited number of cooperative le-sions. Here we report a case of aggressive infant KMT2Ar ALL harbouring additional rare IKZF1 gene fusions. Comprehensive genomic and transcriptomic analyses were performed on sequential samples. This report highlights the genomic complexity of this particular disease and describes the novel gene fusions IKZF1::TUT1 and KDM2A::IKZF1.

Asunto(s)

Proteínas F-Box , Leucemia-Linfoma Linfoblástico de Células Precursoras , Lactante , Recién Nacido , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Transcripción/genética , Fusión Génica , Aberraciones Cromosómicas , Genómica , Factor de Transcripción Ikaros/genética , Proteínas F-Box/genética , Histona Demetilasas con Dominio de Jumonji/genética

RESUMEN

Rearrangements of Janus kinase 2 (JAK2r) form a subtype of acute lymphoblastic leukaemia (ALL) associated with poor patient outcomes. We present a high-risk case of B-cell ALL (B-ALL) where retrospective mRNA sequencing identified a novel GOLGA4-JAK2 fusion gene. Expression of GOLGA4-JAK2 in murine pro-B cells promoted factor-independent growth, implicating GOLGA4-JAK2 as an oncogenic driver. Cells expressing GOLGA4-JAK2 demonstrated constitutive activation of JAK/STAT signalling and were sensitive to JAK inhibitors. This study contributes to the diverse collection of JAK2 fusion genes identified in B-ALL and supports the incorporation of JAK inhibitors into treatment strategies to improve outcomes for this subtype.

Asunto(s)

Autoantígenos/genética , Biomarcadores de Tumor , Janus Quinasa 2/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Animales , Biopsia , Médula Ósea/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Reordenamiento Génico , Predisposición Genética a la Enfermedad , Humanos , Masculino , Ratones , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Pronóstico , Inhibidores de Proteínas Quinasas , Transducción de Señal

RESUMEN

Ruxolitinib (rux) Phase II clinical trials are underway for the treatment of high-risk JAK2-rearranged (JAK2r) B-cell acute lymphoblastic leukemia (B-ALL). Treatment resistance to targeted inhibitors in other settings is common; elucidating potential mechanisms of rux resistance in JAK2r B-ALL will enable development of therapeutic strategies to overcome or avert resistance. We generated a murine pro-B cell model of ATF7IP-JAK2 with acquired resistance to multiple type-I JAK inhibitors. Resistance was associated with mutations within the JAK2 ATP/rux binding site, including a JAK2 p.G993A mutation. Using in vitro models of JAK2r B-ALL, JAK2 p.G993A conferred resistance to six type-I JAK inhibitors and the type-II JAK inhibitor, CHZ-868. Using computational modeling, we postulate that JAK2 p.G993A enabled JAK2 activation in the presence of drug binding through a unique resistance mechanism that modulates the mobility of the conserved JAK2 activation loop. This study highlights the importance of monitoring mutation emergence and may inform future drug design and the development of therapeutic strategies for this high-risk patient cohort.