![]() ![]() 5 In addition, being a potential ALL biomarker, miR128a was characterized as a regulator of stemness and differentiation of leukemic cells. Notably, some miRNAs seem to control expression of the MLL-AF4 fusion protein, but no miRNA has been functionally validated as a critical fusion protein downstream target. ![]() Previous studies identified several aberrantly expressed miRNAs in MLL-AF4 + ALL. Collectively, Malouf et al identified 2 MLL-AF4–regulated and functionally relevant miRNAs (miR-128a, miR-130b) targeting 2 critical downstream effectors that contribute to malignant transformation of fetal liver–derived hematopoietic cells. ![]() Transplant experiments in which miRNA knockdown was combined with target overexpression suggest that induction, as well as maintenance, of the disease phenotype is miRNA dependent and involves downregulation of NR2F6 and SGMS1. NR2F6 and SGMS1 expression was downregulated in tumor cells of pMIRH-128a and pMIRH-130b mice overexpression of these genes decreased proliferation or induced apoptosis of human MLL-AF4 + ALL cell lines, respectively. Malouf et al also identified several candidate target genes that may mediate the leukemic activity of miR-128 (including the nuclear orphan receptor NR2F6 gene), miR-130b, or both (including the sphingomyelin synthase 1 gene). Further transplantation experiments demonstrated that lympho-myeloid progenitors (LMPPs) allowed the propagation of pMIRH-130b mixed B-cell/myeloid leukemia, whereas Lin-Sca1 +/−Il7 +Kit + blasts maintained pro–B-ALL disease of pMIRH-128a mice. Knockdown experiments showed that, although miR-128a seemed to be critical for initiation of the disease, miR-130b was essential for its maintenance. Comparative transcriptomic analysis of tumor cells from diseased mice revealed the expression of several well-known MLL-rearranged leukemia-associated target genes, including Meis1, Runx1 ( pMIRH-128a mice), HoxA9, Flt3 ( pMIRH-130b mice), Cdk6, and Bcl2. Similar to MLL-AF4 + human ALL, pMIRH-128a– and pMIRH-130b–transplanted mice showed significant leptomeningeal tumor cell infiltration. pMIRH-130b mice presented with a mixed B-cell/myeloid malignancy, whereas pMIRH-128a mice developed pro–B-cell ALL. Transplantation of Mll-AF4 + LSK cells virally expressing miR-128a ( pMIRH-128a) or miR-130b ( pMIRH-130b) induced a hematologic malignancy in mice with increasing penetrance upon propagation into secondary and tertiary recipients. Both miRNAs increased the clonogenic B-cell potential of Mll-AF4 + cells. To address the role of these miRNAs in transformation, the investigators overexpressed them in lineage-marker–depleted Sca1 +Kit + (LSK) fetal liver cells from targeted Mll-AF4 invertor mice (see figure). Knockdown of miR-128a and/or miR-130b significantly impaired proliferation of human MLL-AF4 + cell lines, and inhibition of miR-130a significantly impaired disease initiation by the pediatric MLL-AF4 + SEM ALL cell line in immunodeficient NOD- scid IL2Rgamma null (NSG) mice. 1 MLL-AF4 binding upstream of the miR-128a and miR-130b transcriptional start sites suggested direct regulation. ![]() Malouf et al found 2 miRNAs (miR-128a, miR-130b) that were significantly upregulated in tumor cells from pediatric MLL-AF4 + ALL patients. Targeting of Mll-AF4 in early fetal HSPCs enhanced the lymphoid potential of primed multipotent cells but was insufficient by itself to induce leukemia. In an earlier study, Barrett et al used a conditional invertor mouse line for cell-specific expression of an Mll-AF4 fusion protein. 3 Detection of the MLL-AF4 fusion protein in CD34 +/CD19 − fetal hematopoietic stem or progenitor cells or in fetal cells before hematologic specification suggests that there is a window of opportunity during development for the MLL-AF4 fusion protein to immortalize hematopoietic stem and progenitor cells (HSPCs). The small number of potentially cooperating genetic lesions suggests that MLL-AF4 is sufficient to induce infant ALL. 2 Detection of the gene fusion in neonatal blood spots indicates that MLL-rearranged infant ALL originates in utero. 1 Mixed lineage leukemia (MLL) gene fusions are the molecular hallmark of infant acute lymphoblastic leukemia (ALL) and are present in tumor cells in up to 80% of patients. In this issue of Blood, Malouf et al characterize 2 microRNAs (miRNAs) that are effectors of malignant transformation by the MLL-AF4 fusion protein. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |