Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors

Abstract

ABD cases) possibly representing early maturation arrest before the onset of T-cell receptor rearrangements.12

SET-NUP214 is a recurrent γδ lineage-specific fusion transcript associated with corticosteroid/chemotherapy resistance in adult T-ALL

“…The poor prognosis of ETP phenotype, however, is increasingly contested in adult 21 and even pediatric T-ALL. 22 We performed SET-NUP214 RT-PCR screening in 22 AML overexpressing HOXA genes, including 5 minimally differentiated AML (French-American-British AML-M0) patients. One AML-M0 patient was SET-NUP214-positive.…”

ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia

“…[3][4][5][6] Notably, the recently described early T-cell precursor (ETP)-acute lymphoblastic leukemia (ALL) patients 7 have leukemic cells that show an early block in T-cell differentiation and significantly overlap with LYL1-positive T-ALL 4 and MEF2C-dysregulated immature T-ALL. 5,8 These immature T-cell leukemias often express myeloid markers such as CD13 and CD33, and show a transcriptional program related to hematopoietic stem cells and myeloid progenitors. 5 Importantly, these tumors are associated with poor prognosis and reduced overall survival.…”

Novel biological insights in T-cell acute lymphoblastic leukemia

“…Most importantly, the initial study that defined ETP-ALL as a novel immature subtype of pediatric human T-ALL, reported an extremely poor clinical course for these patients with 10-year overall survival rates of 19% for ETP-ALL patients as compared to 84% for other T-ALL subtypes [43]. Although the poor clinical characteristics of this leukemic subtype were subsequently validated in a variety of independent patient series from different international pediatric T-ALL treatment protocols [24,[43][44][45][46], more recent work has started to question the prognostic relevance of this aggressive T-ALL subtype [23,47]. In that context, a very recent and large study on 1144 pediatric T-ALL patients enrolled in the Children's Oncology Group (COG) Study AALL0434 suggested that, despite significantly higher rates of induction failure, pediatric ETP-ALL patients, as defined by flow cytometry in a single reference laboratory, show identical 5-year event-free and overall survival rates as compared to non-ETP-ALLs [48].…”

“…These studies showed that the genetic landscape of immature T-ALL is highly heterogeneous with aberrant expression of the MEF2C gene [23,24], genetic alterations in hematopoietic transcription factors such as RUNX1, GATA3, BCL11B, PU.1 and ETV6 [24], activating mutations in critical mediators of cytokine receptor and RAS signaling, including NRAS, KRAS, FLT3, IL7R, JAK1, JAK3, SH2B3 and BRAF; as well as mutations in the epigenetic regulators EZH2, EED, SUZ12, MLL2, BMI1, SETD2 and EP300; as well as mutations in the dynamin coding gene DNM2 [8,25]. In addition, immature T-ALLs present with lower frequencies of the prototypical NOTCH1 mutations, which occur in the majority of mature T-ALL patient samples and are considered one of the hallmarks of human T-cell transformation.…”