Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0598766 (
leukemogenesis
)
4,065
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Chromosomal translocations involving the mixed lineage leukemia (MLL) gene lead to the development of acute leukemias. Constitutive HOX gene activation by MLL fusion proteins is required for MLL-mediated
leukemogenesis
; however, the underlying mechanisms remain elusive. Here, we show that
chromobox homolog 8
(
CBX8
), a Polycomb Group protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and
leukemogenesis
. Conversely, both
CBX8
ablation and specific disruption of the
CBX8
interaction by point mutations in MLL-AF9 abrogate HOX gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that
CBX8
plays an essential role in MLL-AF9 transcriptional regulation and
leukemogenesis
.
...
PMID:CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. 2209 47
The cell of origin, defined as the normal cell in which the transformation event first occurs, is poorly identified in leukemia, despite its importance in understanding of
leukemogenesis
and improving leukemia therapy. Although hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were used for leukemia models, whether their self-renewal and differentiation potentials influence the initiation and development of leukemia is largely unknown. In this study, the self-renewal and differentiation potentials in 2 distinct types of HSCs (HSC1 [CD150
+
CD41
-
CD34
-
Lineage
-
Sca-1
+
c-Kit
+
cells] and HSC2 [CD150
-
CD41
-
CD34
-
Lineage
-
Sca-1
+
c-Kit
+
cells]) and 3 distinct types of HPCs (HPC1 [CD150
+
CD41
+
CD34
-
Lineage
-
Sca-1
+
c-Kit
+
cells], HPC2 [CD150
+
CD41
+
CD34
+
Lineage
-
Sca-1
+
c-Kit
+
cells], and
HPC3
[CD150
-
CD41
-
CD34
+
Lineage
-
Sca-1
+
c-Kit
+
cells]) were isolated from adult mouse bone marrow, and examined by competitive repopulation assay. Then, cells from each population were retrovirally transduced to initiate MLL-AF9 acute myelogenous leukemia (AML) and the intracellular domain of NOTCH-1 T-cell acute lymphoblastic leukemia (T-ALL). AML and T-ALL similarly developed from all HSC and HPC populations, suggesting multiple cellular origins of leukemia. New leukemic stem cells (LSCs) were also identified in these AML and T-ALL models. Notably, switching between immunophenotypical immature and mature LSCs was observed, suggesting that heterogeneous LSCs play a role in the expansion and maintenance of leukemia. Based on this mouse model study, we propose that acute leukemia arises from multiple cells of origin independent of the self-renewal and differentiation potentials in hematopoietic stem and progenitor cells and is amplified by LSC switchover.
...
PMID:Mouse acute leukemia develops independent of self-renewal and differentiation potentials in hematopoietic stem and progenitor cells. 3073 2
