Mechanistic Studies Of Hematopoietic Cells Malignant Transformation

Acute myeloid leukemia and diffuse large B cell lymphoma are common malignant diseases of the blood system,both of them are derived from malignant transformation of hematopoietic cell.Genome instability of these cells generates subsequent pathogenic events,such as gene mutation and chromosome translocation,leading to the malignant transformation of hematopoietic cells,characterized by increasing proliferation and differentiation arrest,eventually causing the happening of the disease.In this paper,the malignant transformation mechanism of AML and DLBCL are studied respectively 1)Mechanistic study on the sternness maintenance and differentiation promoting of acute myeloid leukemia cells:based on the theory of heterogeneity and spontaneous differentiation of leukemia cells,we found that the AML1/ET09a leukemia cells consist of three subclones which are in different differentiation stages,with the spontaneously erythroid-terminal-differentiation potential.2)The degradation of Blimp-1 protein in Diffuse Large B-cell Lymphoma:through the study on the stability of Blimp-1 protein,we found that HSP70 inhibitors can improve thee stability of mutant protein(P84R,I107K)to achieve the effect of anti-tumorPart ⅠMechanistic study on the stemness maintenance and differentiation promoting of acute myeloid leukemia cellsChromosomal translocation 8;21 is found in 40%of the FAB M2 subtype of acute myeloid leukemia(AML).Currently,studies of AML1-ETO related leukemia mainly focus on the molecular mechanism of its pathogenesis.Recent studies suggest that contemporary therapeutic methods are ineffective to eradicate the specific leukemia cellular subsets that possess the malignant stemness.Basing on spontaneous hierarchical differentiation of leukemia cells,by analysing leukemia cells phenotype of the mouse model of AML-M2b,we found that AE9a leukemia cells possess some features of erythroid cells and have the erythroid differentiation potential,and the CD43 negative subset of AE9a leukemia cells are terminal differented erythroid cells.We further combined c-Kit and CD43,two cell surface molecular markers,to divide leukemia cells into three subsets,and found the three subsets are at different stages of spontaneous differentiation.The phenotype,biological function and transcriptome expression of the three subsets are heterogeneous and hierarchical,and the sternness of leukemia cells are periodically attenuating along with spontaneously differentiatingPart ⅡThe degradation of Blimp-1 protein in Diffuse Large B-cell LymphomaDiffuse large B cell lymphoma(DLBCL)is one of the most common Non Hodgkin lymphoma(NHL),and activated B-cell-like DLBCL,one of the subtypes,has poor response to current treatments.Blimp-1 instability is documented in specific aggressive cases of B-cell lymphoma(ABC-DLBCL),yet the underlying mechanisms and therapeutic potential remain unexplored.Here,we show that representative N-terminal misfolding mutations in ABC-DLBCL render Blimp-1s susceptible to proteasome-mediated degradation but sparing their transcription-regulatory activity.Mechanistically,the degradation of lymphoma-associated mutants is accelerated by a pathway-subversion to Hrdl-mediated cytoplasmic sequestration and ubiquitination.Screening experiments identified HSP70 that selects the mutant Blimp-1s for Hrdl association,and HSP70 inhibition restores their nuclear accumulation and oncorepressor activities without disturbing normal B cell maturation.Collectively,these results implicate HSP-Hrdl axis as a potential therapeutic target for restoring the oncorepressor activity of lymphoma-associated Blimp-1 mutants.