T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive class of hematologic tumors caused by malignant transformation and abnormal proliferation of T-cell progenitors. T-ALL represents 10-15% of pediatric ALL and, despite the improved survival rate during the last decades, 20% of cases still experience relapsed and therapy failure. MYC serves as a pivotal oncogene in the pathogenesis of T-ALL that can be activated through a number of direct and indirect mechanisms. For example, a rare subgroup of primary T-ALL (~1%) is characterized by T cell receptor (TCR) driven translocations that cause massive activation of the MYC oncogene and present an unfavorable prognosis, rapid disease progression and poor response to conventional therapy.
Here, we performed detailed molecular genetic characterization of an extensive series of primary T-ALL that present TCR driven MYC translocations and evaluated new therapeutic strategies for this poor prognostic subtype of human leukemia.
Molecular genetic characterization of a cohort of 28 pediatric T-ALL patients carrying the t(8;14)(q24;q11) translocation was performed by copy number profiling, gene expression and mutational screening. Xenograft experiments with primary patient material were used to evaluate the therapeutic relevance of JQ1 in the context of MYC translocation positive T-ALL.
Copy number analysis of MYC translocated T-ALL cases revealed loss of the previously reported T-ALL tumor suppressor genes PTEN (18%), CDKN2A/B (68%) and LEF1 (7%). Moreover, about 30% of patients harbored genomic deletions that cause aberrant activation of the SIL-TAL1 or LMO2 oncogenes. Interestingly, sequencing analysis revealed no aberrations in NOTCH1 or FBXW7 and a high number (30%) of loss-of-function mutations targeting PTEN. Therefore, TCRAD-MYC translocation positive T-ALL seems to represent a NOTCH1 independent subtype of leukemia that is frequently addicted to activated PI3K/AKT signaling. In line with this notion, the t(8;14)(q24;q11) positive T-ALL cell lines KE-37 and MOLT16 lack NOTCH1/FBXW7 mutations but both present loss of PTEN. Indeed, these tumor lines show aberrant pAKT activation but lack enhanced NOTCH1 activity at the protein level. In accordance with the frequent identification of TAL1 and/or LMO2 rearrangements, genome-wide transcription profiling analysis revealed that TCRAD-MYC positive T-ALL showed a uniform gene expression signature reminiscent of late cortical thymocyte T-ALL that express CD4, CD8 and membrane CD3. Importantly, gene set enrichment analysis revealed a negative enrichment of NOTCH1 target genes in MYC translocated late cortical T-ALLs, including NOTCH3, HES4, DLL4, PTCRA and DTX1.
From a therapeutic perspective, in vitro drug sensitivity screening showed that MYC rearranged T-ALL cell lines were amongst the most sensitive to JQ1 treatment (IC50 values: MOLT16, 199nM; KE37, 497nM). MYC mRNA and protein downregulation were confirmed after JQ1 treatment for both the lines. Moreover, in vivo drug treatment experiments using xenografts generated from primary t(8;14)(q24;q11) positive T-ALL patients cells showed the in vivo activity of the JQ1 against this aggressive subtype of human T-ALL, as evaluated by percentage of leukemic blasts in blood or bone marrow and spleen size. Given the high frequency of genetic abnormalities targeting the PI3K/AKT pathway in these NOTCH1 independent human T-ALL, we are currently evaluating the synergistic activity of JQ1/MK-2206 combination therapy using the same in vivo model systems.
In this study, we identified TCRAD-MYC rearranged T-cell leukemia as a novel subclass of NOTCH1-independent late cortical T-ALL that frequently depend on aberrant PI3K/AKT signaling. Moreover, we showed that JQ1 might serve as a promising new therapeutic strategy for the treatment of this high-risk subtype of pediatric leukemia.
Citation Format: Gloria Milani, Kaat Durinck, Filip Matthijssens, Sofie Peirs, Tim Pieters, Lindy Reunes, Beatrice Lintermans, Niels Vandamme, Tim Lammens, Yunlei Li, Claire Schwab, Susana Raimondi, Barbara De Moerloose, Yves Benoit, Geert Berx, Christine Harrison, Giuseppe Basso, Helene Cavé, Rosemary Sutton, Vahid Asnafi, Charles Mullighan, Jules Meijerink, Mignon Loh, Pieter Van Vlierberghe. Genetic characterization and therapeutic targeting of MYC translocated pediatric T-cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B21.