Similar Datasets
Project description:MLL rearrangements (MLLr) are the most common cause of congenital and infant leukemias. MLLr arise prior to birth and require very few cooperating mutations for transformation, yet congenital leukemias are 10-fold less common than infant leukemias and >100-fold less common than childhood leukemias overall. This raises the question of whether mechanisms exist to suppress leukemic transformation during fetal life. Here, we show that in mice, fetal MLL::ENL exposure creates a heritable, leukemia-resistant state. MLL::ENL imposes a negative selective pressure on fetal hematopoietic progenitors that persists after birth to suppress transformation. These changes do not occur when MLL::ENL is induced shortly after birth, and transformation proceeds efficiently in that context. The fetal barrier to transformation is enforced by MLL3. It can be bypassed by cooperating mutations or inactivation of MLL3. Heritable, fetal protection against leukemic transformation may explain the low incidence of congenital leukemias in humans despite prenatal MLL rearrangement.
2025-09-19 | GSE291037 | GEO
Project description:MLL rearrangements (MLLr) are the most common cause of congenital and infant leukemias. MLLr arise prior to birth and require very few cooperating mutations for transformation, yet congenital leukemias are 10-fold less common than infant leukemias and >100-fold less common than childhood leukemias overall. This raises the question of whether mechanisms exist to suppress leukemic transformation during fetal life. Here, we show that in mice, fetal MLL::ENL exposure creates a heritable, leukemia-resistant state. MLL::ENL imposes a negative selective pressure on fetal hematopoietic progenitors that persists after birth to suppress transformation. These changes do not occur when MLL::ENL is induced shortly after birth, and transformation proceeds efficiently in that context. The fetal barrier to transformation is enforced by MLL3. It can be bypassed by cooperating mutations or inactivation of MLL3. Heritable, fetal protection against leukemic transformation may explain the low incidence of congenital leukemias in humans despite prenatal MLL rearrangement.
2025-09-19 | GSE291038 | GEO
Project description:MLL rearrangements (MLLr) are the most common cause of congenital and infant leukemias. MLLr arise prior to birth and require very few cooperating mutations for transformation, yet congenital leukemias are 10-fold less common than infant leukemias and >100-fold less common than childhood leukemias overall. This raises the question of whether mechanisms exist to suppress leukemic transformation during fetal life. Here, we show that in mice, fetal MLL::ENL exposure creates a heritable, leukemia-resistant state. MLL::ENL imposes a negative selective pressure on fetal hematopoietic progenitors that persists after birth to suppress transformation. These changes do not occur when MLL::ENL is induced shortly after birth, and transformation proceeds efficiently in that context. The fetal barrier to transformation is enforced by MLL3. It can be bypassed by cooperating mutations or inactivation of MLL3. Heritable, fetal protection against leukemic transformation may explain the low incidence of congenital leukemias in humans despite prenatal MLL rearrangement.
2025-09-19 | GSE291040 | GEO
Project description:Heritable fetal protection against MLL::ENL-driven leukemogenesis depends on MLL3
| PRJNA1231439 | ENA
Project description:Heritable fetal protection against MLL::ENL-driven leukemogenesis depends on MLL3 [scATAC-seq]
| PRJNA1231437 | ENA
Project description:Heritable fetal protection against MLL::ENL-driven leukemogenesis depends on MLL3 [scRNA-seq]
| PRJNA1231436 | ENA
Project description:Heritable fetal protection against MLL::ENL-driven leukemogenesis depends on MLL3 [Bulk RNA-seq]
| PRJNA1231447 | ENA
Project description:Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism underlying aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their trithorax homology domain 2 (THD2) in various human cell lines. MLL proteins associated with the HBO1 complex through multiple contacts mediated mainly by the ING4/5 and PHF16 subunits in a chromatin-bound context where histone H3 lysine 4 tri-methylation marks were present. Of the many MLL fusions, MLL-ELL particularly depended on the THD2-mediated association with the HBO1 complex for leukemic transformation. The C-terminal portion of ELL provided a binding platform for multiple factors including AF4, EAF1, and p53. MLL-ELL activated gene expression in murine hematopoietic progenitors by loading an AF4/ENL/P-TEFb (AEP) complex onto the target promoters wherein the HBO1 complex promoted the association with AEP complex over EAF1 and p53. Moreover, the NUP98-HBO1 fusion protein exerted its oncogenic properties via interaction with MLL but not its intrinsic HAT activity. Thus, the interaction between the HBO1 complex and MLL is an important nexus in leukemic transformation, which may serve as a therapeutic target for drug development.
| S-EPMC8387021 | biostudies-literature
Project description:Chromosomal rearrangements of the mixed-lineage leukemia gene MLL1 are the hallmark of infant acute leukemia. The granulocyte-macrophage progenitor state forms the epigenetic basis for myelomonocytic leukemia stemness and transformation by MLL-type oncoproteins. Previously, it was shown that the establishment of murine myelomonocytic MLL-ENL transformation, but not its maintenance, depends on the transcription factor C/EBPα, suggesting an epigenetic hit-and-run mechanism of MLL-driven oncogenesis. Here, we demonstrate that compound deletion of Cebpa/Cebpb almost entirely abrogated the growth and survival of MLL-ENL-transformed cells. Rare, slow-growing, and apoptosis-prone MLL-ENL-transformed escapees were recovered from compound Cebpa/Cebpb deletions. The escapees were uniformly characterized by high expression of the resident Cebpe gene, suggesting inferior functional compensation of C/EBPα/C/EBPβ deficiency by C/EBPε. Complementation was augmented by ectopic C/EBPβ expression and downstream activation of IGF1 that enhanced growth. Cebpe gene inactivation was accomplished only in the presence of complementing C/EBPβ, but not in its absence, confirming the Cebpe dependency of the Cebpa/Cebpb double knockouts. Our data show that MLL-transformed myeloid cells are dependent on C/EBPs during the initiation and maintenance of transformation.
| S-EPMC7652399 | biostudies-literature
Project description:The Ten Eleven Translocation 1 (TET1) gene encodes an epigenetic modifying molecule that is involved in demethylation of 5-methylcytosine. In hematological malignancies, loss-of-function mutations of TET2, which is one of the TET family genes including TET1, are frequently found, while the mutations of TET1 are not. However, clinical studies have revealed that TET1 is highly expressed in some cases of the hematological malignancies including acute myeloid leukemia. Indeed, studies by mouse models using conventional Tet1 knockout mice demonstrated that Tet1 is involved in myeloid leukemogenesis by Mixed Lineage Leukemia (MLL) fusion gene or TET2 mutant. Meanwhile, the other study showed that Tet1 is highly expressed in hematopoietic stem cells (HSCs), and that deletion of Tet1 in HSCs enhances potential self-renewal capacity, which is potentially associated with myeloid leukemogenesis. To examine the role of Tet1 in myeloid leukemogenesis more precisely, we generated novel conditional Tet1-knockout mice, which were used to generate the compound mutant mice by crossing with the inducible MLL-ENL transgenic mice that we developed previously. The leukemic immortalization in vitro was not critically affected by conditional ablation of Tet1 in HSCs with the induced expression of MLL-ENL or in hematopoietic progenitor cells retrovirally transduced with MLL-ENL. In addition, the leukemic phenotypes caused by the induced expression of MLL-ENL in vivo was not also critically affected in the compound mutant mouse model by conditional ablation of Tet1, although we found that the expression of Evi1, which is one of critical target genes of MLL fusion gene, in tumor cells was remarkably low under Tet1-ablated condition. These results revealed that Tet1 was dispensable for the myeloid leukemogenesis by MLL-ENL, suggesting that the therapeutic application of Tet1 inhibition may need careful assessment.
| S-EPMC7951824 | biostudies-literature