The Hoxa9 and Meis1 genes represent important oncogenic collaborators activated in a significant proportion of human leukemias with genetic alterations in the MLL gene. In this study, we show that the transforming property of Meis1 is modulated by 3 conserved domains, namely the Pbx interaction motif (PIM), the homeodomain, and the C-terminal region recently described to possess transactivating properties. -HOXA9) that characterize myeloid leukemias in human and mice; (3) the overexpression of HOXA7 and HOXA9 in several MLL-induced human leukemias 11,12 ; (4) the distinctly high correlation between high levels of HOXA9 expression and poor prognosis in human acute myeloid leukemia (AML) 13 ; and (5) coexpression of BCR-ABL and NUP98-HOXA9 in a significant number of human leukemic specimens, 14 and a recent proof of their genetic interaction. 15 Together, these studies establish a direct and indirect role for multiple Hox genes in human leukemias, and highlight the importance of revealing the molecular bases of Hox-induced transformation.Some insight into the molecular mechanisms of Hox-induced transformation may be gained from studies of Hox cofactors, members of the TALE (for 3-amino-acid loop extension) family of homeodomain proteins. Of interest, founders of 2 subgroups within this family, namely PBX1 16,17 and Meis1, 18 were identified based on their participation in human and mouse leukemia, respectively.Hox, Pbx, and Meis participate in a multiprotein interaction network. The cooperative interaction between Pbx and Hox proteins enhances the DNA binding affinity and specificity of Hox proteins 19 and is essential for at least some of the Hox-dependent developmental programs. [20][21][22] In contrast, a functional role for a dimeric Hox-Meis complex has so far not been established. 23 Members of the Meis family can form complexes with Pbx in DNA-dependent and independent manners. [24][25][26] Interaction with Meis induces nuclear localization of Pbx by preventing its nuclear export 27,28 and promoting nuclear import. 29,30 Indirect interaction between Hox and Meis proteins was established by the identification of Hox-Pbx-Meis heterotrimeric complexes. 26 PBX1 is involved as part of the fusion E2a-PBX1 oncoprotein in a high proportion of human pre-B leukemias. 16,17 We recently generated a mouse model of E2a-PBX1-induced pre-B-cell leukemia, and showed that the Hoxa locus was targeted by murine Moloney leukemia virus (MMLV) in the majority of the leukemias analyzed. 31 These leukemias were characterized by aberrant expression of Hoxa genes, and all expressed high levels of Hoxa7, thus pointing to a genetic interaction between E2a-PBX1 and Hoxa genes. In support of these findings, we
Graphical AbstractHighlights d ITGA3 + cells positively identify LT-repopulating HSCs in cultured cord blood cells d ITGA3 + cells display durable multipotentiality d ITGA3 + is functionally required for the LT-engraftment ability of CB cells SUMMARY Transplantation of expanded hematopoietic stem cells (HSCs) and gene therapy based on HSC engineering have emerged as promising approaches for the treatment of hematological diseases. Nevertheless, the immunophenotype of cultured HSCs remains poorly defined. Here, we identify Integrin-a3 (ITGA3) as a marker of cultured human HSCs. Exploiting the pyrimidoindole derivative UM171 to expand cord blood (CB) cells, we show that ITGA3 expression is sufficient to separate the primitive EPCR + CD90 + CD133 + CD34 + CD45RA À HSC population into two functionally distinct fractions presenting mostly short-term (ITGA3 À ) and both short-term and long-term (ITGA3 + ) repopulating potential. ITGA3 + cells exhibit robust multilineage differentiation potential, serial reconstitution ability in immunocompromised mice, and an HSC-specific transcriptomic signature. Moreover, ITGA3 expression is functionally required for the long-term engraftment of CB cells. Altogether, our results indicate that ITGA3 is a reliable marker of cultured human long-term repopulating HSCs (LT-HSCs) and represents an important tool to improve the accuracy of prospective HSC identification in culture.
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