Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia

Abstract

Trib1 has been identified as a myeloid oncogene in a murine leukemia model. Here we identified a TRIB1 somatic mutation in a human case of Down syndrome-related acute megakaryocytic leukemia. The mutation was observed at well-conserved arginine 107 residue in the pseudokinase domain. This R107L mutation remained in leukocytes of the remission stage in which GATA1 mutation disappeared, suggesting the TRIB1 mutation is an earlier genetic event in leukemogenesis. The bone marrow transfer experiment showed that acute myeloid leukemia development was accelerated by transducing murine bone marrow cells with the R107L mutant in which enhancement of ERK phosphorylation and C/EBP␣ degradation by Trib1 expression was even greater than in those expressing wild-type. These results suggest that TRIB1 may be a novel important oncogene for Down syndrome-related acute megakaryocytic leukemia. (Blood. 2012; 119(11):2608-2611) IntroductionThe Down syndrome (DS) patients are predisposed to developing myeloid leukemia, and those patients frequently exhibit GATA1 mutations. 1 However, it is proposed that the GATA1 mutation is important for transient leukemia in DS but not sufficient for full-blown leukemia, suggesting that additional genetic alterations are needed. 1 Therefore, it is important to search the subsequent genetic changes for DS-related leukemia (ML-DS) to predict malignant transformation and prognosis of the patients.Trib1 has been identified as a myeloid oncogene that cooperates with Hoxa9 and Meis1 in murine acute myeloid leukemia (AML). 2 As a member of the tribbles family of proteins, TRIB1 interacts with MEK1 and enhances ERK phosphorylation. 2,3 Moreover, TRIB1 promotes degradation of C/EBP family transcription factors, including C/EBP␣, an important tumor suppressor for AML, and we observed that degradation of C/EBP␣ by Trib1 is mediated by its interaction with MEK1. 4 Thus, TRIB1 plays an important role in the development of AML by modulating both the RAS/MAPK pathway and C/EBP␣ function together with Trib2 that has also been identified as a myeloid-transforming gene. 5 Potential involvement of TRIB1 in human leukemia has been reported in cases of AML with 8q34 amplification in which both c-MYC and TRIB1 are included in the amplicon. 6 The enhancing effect of TRIB1 on the MAPK signaling suggests that TRIB1 alterations may be related to AML cases, which do not show any mutations in the pathway members, such as FLT3, c-Kit, or Ras. In this report, we identified a novel somatic mutation of TRIB1 in a case of human acute megakaryocytic leukemia developed in DS (DS-AMKL). Retrovirus-mediated gene transfer followed by bone marrow transfer indicated that the mutation enhanced leukemogenic activity and MAPK phosphorylation by TRIB1. Patient 84 showed trisomy 21 and extensive leukocytosis at birth. Hematologic findings revealed the white blood cell count to be 148 ϫ 10 9 /L, including 87% myeloblasts, a hemoglobin level of 19.4 g/dL, and a platelet count of 259 ϫ 10 9 /L. Patent ductus arteriosus and atrial septal defect...

Competition between members of the tribbles pseudokinase protein family shapes their interactions with mitogen activated protein kinase pathways

“…However, we have previously reported a concentration dependent, bi-phasic regulatory role for these proteins23 and potentiation of TRIB mediated potentiation of MEK1/ERK signalling has also been reported1347. Whilst it is possible that complex alterations between specific MAPK complexes due to changes in specific TRIB levels could explain these results, such hypothesis is yet to be tested, both experimentally and theoretically, via computational models.…”

TRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha

“…6A). Furthermore, a gain of function mutation (L107R) 26 had no detectable impact on the interaction.

Figure 6Mapping of the TRIB1 interface associating with HNF4A. Recombinant TRIB1 or fragments thereof, harboring the indicated mutations or deletions were incubated in the presence of HNF4A-expressing HEK293T lysates.

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Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

“…Interestingly, when this amino acid was analyzed across the kinome [61], an Arg or Lys residue was found in approximately 35% of human kinases, with Leu representing the most common single amino acid, accounting for approximately 25% of (pseudo)kinases in the human ePK family. Although mechanistic effects of an R107L substitution are not fully understood in TRIB1, enhancement of both ERK phosphorylation and C/EBPα degradation have been demonstrated in an R107L TRIB1 murine bone marrow model of AML [62]. Based on the crystal structures of PKA and TRIB1, we speculate that this mutation contributes to abnormal TRIB1 pseudokinase function by disrupting regulatory protein interactions with interacting partners, such as MAPKK family members [46], Ubiquitin E3 ligases, or cis -acting flanking regulatory segments in TRIB itself.…”