STAT3 mediates oncogenic addiction to TEL-AML1 in t(12;21) acute lymphoblastic leukemia

Abstract

Key Points• STAT3 activity is necessary for TEL-AML1 leukemia maintenance.• TEL-AML1 induces STAT3 activation via RAC1 and leading to induction of MYC expression.The t(12;21)(p13;q22) translocation is the most common chromosomal abnormality in pediatric leukemia. Although this rearrangement involves 2 well-characterized transcription factors, TEL and AML1, the molecular pathways affected by the result of the translocation remain largely unknown. Also in light of recent studies showing genetic and functional heterogeneities in cells responsible for cancer clone maintenance and propagation, targeting a single common deregulated pathway may be critical for the success of novel therapies. Here we describe a novel signaling pathway that is essential for oncogenic addiction in TEL-AML1 leukemia. Our data indicate a direct role for TEL-AML1, via increasing the activity of RAC1, in regulating the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which results in transcriptional induction of MYC. We demonstrate that human leukemic cell lines carrying this translocation are highly sensitive to treatment with S3I-201, a specific STAT3 inhibitor, and, more interestingly, that primary human leukemic samples are also responsive to the drug in the same concentration range. Thus, STAT3 inhibition represents a promising possible therapeutic strategy for the treatment of TEL-AML1 leukemia. (Blood. 2013;122(4):542-549)

Tiam1/Rac1 signals contribute to the proliferation and chemoresistance, but not motility, of chronic lymphocytic leukemia cells

“…53 Furthermore, Rac1 is involved in regulating the phosphorylation of the signal transducer and activator of transcription 3, which results in the transcriptional induction of c-Myc. 55 It is conceivable that a similar mechanism accounts for the parallel induction of Tiam1 and c-Myc in CLL cells.…”

Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse

“…First of all, E/R can reduce sensitivity to the inhibition of proliferation mediated by TGF-β signaling, suggesting that the dysregulated immune responses to infection might promote the malignant evolution of pre-leukemic clones [70]. The E/R fusion gene can also induce signal transducer and activator of transcription 3 ( STAT3 ) activation, aiding to the self-renewal and leukemogenic activity of leukemia cells [77, 78]. STAT3 activation has been shown to transcriptionally induce MYC [77] and SMAD7 [78] gene expression in E/R leukemic cells.…”

Molecular Genetic Studies on 167 Pediatric ALL Patients from Different Areas of Pakistan Confirm a Low Frequency of the Favorable Prognosis Fusion Oncogene TEL-AML1 (t 12; 21) in Underdeveloped Countries of the Region

“…Pediatric ALL is associated with many genetic abnormalities which have huge clinical implications in prognostic stratification, anti-leukemic drug selection at different treatment phases and follow-up of the treatment (Mangolini et al, 2013;Urayama et al, 2013) A common acquired genetic lesion in ALL patients is TEL-AML1 fusion oncogene, resulted due to t (12; 21) (p13; q22), that have previously been described among chromosomal translocations specific for lymphoid malignancies (Tsuzuki and Seto, 2013). In several studies, the application of molecular and cytogenetic tools such as fluorescent in situ hybridization (FISH), southern blot analysis, karyotyping and RT-PCR have shown TEL-AML1 fusion transcripts in up to 20-30% of childhood ALL, making it the most common molecular cytogenetic abnormality in pediatric ALL (Lewis, 2007;Hong et al, 2008).…”

“…Significant use of the drug L-asparaginase can benefit the patients with TEL-AML1 acute lymphoid leukemia Iqbal, (2006) and nearly all TEL-AML positive pediatric patients can be cured using intensive treatment protocols containing intensive asparaginase and high-dose methotrexate (Pui et al, 2008;Bhojwani et al, 2013). Furthermore, it is clinically established that, as compared to other genetic abnormalities, TEL-AML1 positive pediatric ALL patients shows excellent prognosis and outcome to standard treatment protocols being used in different regions of the world for treatment of this disease (Bhojwani et al, 2013;Mangolini et al, 2013). Thus, determination of TEL-AML1 fusion oncogene status at diagnosis and its percentage among other genetic abnormalities in pediatric ALL patients in a given population can significantly affect the outcome of treatment and can have a significant bearing on disease management policies related to pediatric ALL in a geographic region.…”