Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis

Abstract

IntroductionCarcinogenesis is a consecutive process of multiple genetic and epigenetic alterations that affect the target cell to acquire growth advantages and dysregulated growth from tissue environment. 1 Plenty of genetic mutations have been discovered in both human and animal cancers. It should be noted that the mutations are cell-type specific and that there is specific genetic cooperation in the multi-step evolution of premalignant cells. The combination of genetic mutations alters cell fate, and specific genetic cooperation is therefore important for tumor phenotypes and biologic behaviors of cancer cells.Proper expression of AbdB-like Hox genes is a key molecular process in hematopoiesis and their deregulation perturbs myeloid differentiation, eventually resulting in leukemia with several cooperative genetic events. 2 One of the important Hox genes in myeloid leukemogenesis is Hoxa9, which has been identified as a target for ecotropic retroviral integration in BXH2 murine AML 3 as well as a fusion partner of NUP98 in human AML with t(7;11)(p15;p15) translocation. 4,5 Importantly, cooperative activation of the Hox cofactor Meis1 is important for both Hoxa9-and NUP98-HOXA9-induced transformation of murine bone marrow cells. 6,7 Recent studies have suggested that Meis1 might activate Flt3 receptor tyrosine kinase, which plays an important role in myeloid leukemogenesis. [8][9][10] However, it remains to be clarified what kinds of subsequent molecular processes are required for complete leukemogenesis, and it is important to understand subsequent molecular steps that are cooperative for Hoxa9 and Meis1 activation.We have addressed this issue by using retroviral insertional mutagenesis that has been applied for identification of oncogenes and tumor suppressor genes. 11 Plenty of important disease genes have been isolated by this technique and many of the genes are in fact involved in human cancers. Retroviral integration in the bone marrow cells is randomly distributed over the whole genome, and the cells with integrations that contribute growth advantages are subsequently selected and clonally expanded. Cooperative genetic effects in leukemogenesis can be achieved by multi-copy integration of retroviruses. The multiple integrations do not occur simultaneously, but it is likely that the process is consecutive, since such cooperative integrations are extremely rare without any predisposition. When there is a primary genetic alteration in the target cell, genetic cooperation for the first hit can be investigated by this technique. 12 Retrovirus-mediated gene transfer and bone marrow transfer of Hoxa9 and Meis1 induce AML at 100% penetrance. 6,13 In this study we have found that there is clonal selection of the transduced bone marrow cells at the transformation step, and we have systematically cloned retroviral integration sites in Hoxa9/Meis1-induced AML. Inverse polymerase chain reaction (PCR) experiments identified 6 common integration sites (CISs), and candidate cooperative genes for Hoxa9/Meis1 coactivation...

Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation

“…Interestingly, a recent study showed that the combination of Hoxa9 and Meis1 cooperated with Trib1, which enhanced the phosphorylation of ERK, to induce acute leukemia in the BM transplantation assays. 51 Their study is not inconsistent with our findings; thus, the HOX and Ras/Raf/MAPK axes may have central roles in the molecular network of MLL-mediated leukemogenesis, which might be additively affected by other pathways, such as activation of STAT5 (Figure 7). In addition, at least, endogenous expression of Meis1 in A9G cells is also considered to be important in this network, but further analysis will be required to clarify the role of Meis1 in the collaboration between HOX and MAPK axes.…”

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

“…It is worth noting that it has been reported that TRIB3-null animals show upregulation of TRIB1 and TRIB2 in at least some tissues. 39 As TRIB2 is associated with induction of acute myelogenous leukemia 40,41 and TRIB1 with other malignancies, 42,43 changes in the levels of the other Tribbles isoforms may also contribute to the phenotype observed in Trib3 À / À animals.…”

Hox genes in hematopoiesis and leukemogenesis

“…Chief among these are to identify the cell targets within the hematopoietic hierarchy that can respond to Hox pathways and thus give origin to LSCs. The collaborating genes necessary for frank leukemic transformation in concert with Hox remain to be elucidated fully although much progress in this area is being made (Iwasaki et al, 2005;Jin et al, 2007). Crucial for further insight will be the delineation of the target genes regulated by Hox of which there is still little known, and identification of the likely protein interactions, extending beyond the known HOX cofactors, that mediate the transcriptional activity of HOX.…”