The BCR/ABL oncoproteins, the leukemia-specific gene products of the Philadelphia chromosome (Ph1) translocation, induce and maintain the leukemic phenotype through their deregulated tyrosine kinase activity;such activity is essential for recruitment and activation of multiple pathways that transduce signals leading to growth factor-independent proliferation, inhibition of apoptosis, and altered differentiation of myeloid precursor cells. While the mechanisms of activation of the cytoplasmic downstream effectors of BCR/ABL are understood in some detail, much less is known on the pathways leading to transcription factor regulation. In this application we will investigate the BCR/ABL-dependent pathways leading to changes in the expression of the transcription factor c-Myb and assess the role of c-Myb and c-Myb targets in the regulation of proliferation, survival, and differentiation of BCR/ABL-expressing hematopoietic progenitors by: 1) Investigating the role of the F-box protein FBXL-3 in regulating c-Myb levels in p210 BCR/ABL-expressing cells by assessing: a) the mechanisms of FBXL-3-dependent degradation of c-Myb;b) the effects of FBXL-3 in normal and p210BCR/ABL-expressing hematopoietic progenitors. 2) Investigating the requirement of c-Myb in p210BCR/ABL-dependent leukemogenesis by assessing: a) role and requirement of the c-Myb target c-Kit in transformation and leukemogenesis of p210BCR/ABL-expressing c-Myb and c-Myb primitive hematopoietic progenitors;b) cooperation of c-Myb targets c-Kit and Bcl-2 in transformation and leukemogenesis of p210BCR/ABL -expressing c-Myb primitive hematopoietic progenitors. c) effects of the c-Myb target Jak2 , individually and in cooperation with c-Kit, in transformation and leukemogenesis of p210BCR/ABL-expressing hematopoietic progenitors. 3) Investigate the requirement of c-Myb in p190BCR/ABL-dependent leukemogenesis by assessing: a) transformation and leukemogenesis of B-cell progenitor subsets from double transgenic p190BCR/ABL/c-Myb mice;b) leukemogenesis of c-Myb-silenced p190BCR/ABL-expressing Z-181 human B-cell leukemia cells in NOD-SCID mice;c) the role of c-Myb targets identified by microarray hybridization in p190BCR/ABL-dependent leukemogenesis.
Leukemias are malignancies of blood cell progenitors which may be caused by specific chromosomal abnormalities. In chronic myelogenous leukemia and in acute leukemias associated with the Philadelphia chromosome, the BCR/ABL oncogene promotes transformation of hematopoietic cells by activating nuclear proteins such as c-Myb. Understanding the role of c-Myb in leukemogenesis is important for developing therapies based on inhibition of its expression/activity.
|Mariani, Samanta A; Calabretta, Bruno (2014) Leukemia stem cells: Old concepts and new perspectives. Mol Aspects Med 39:102-9|
|Helgason, Gudmundur V; Mukhopadhyay, Arunima; Karvela, Maria et al. (2013) Autophagy in chronic myeloid leukaemia: stem cell survival and implication in therapy. Curr Cancer Drug Targets 13:724-34|
|Pelosi, A; Careccia, S; Lulli, V et al. (2013) miRNA let-7c promotes granulocytic differentiation in acute myeloid leukemia. Oncogene 32:3648-54|
|Ferrari-Amorotti, Giovanna; Fragliasso, Valentina; Esteki, Roza et al. (2013) Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion. Cancer Res 73:235-45|
|Calabretta, Bruno; Salomoni, Paolo (2012) Suppression of autophagy by BCR/ABL. Front Biosci (Schol Ed) 4:453-60|
|Soliera, A R; Mariani, S A; Audia, A et al. (2012) Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1. Leukemia 26:1555-63|
|Waldron, T; De Dominici, M; Soliera, A R et al. (2012) c-Myb and its target Bmi1 are required for p190BCR/ABL leukemogenesis in mouse and human cells. Leukemia 26:644-53|
|Fragliasso, Valentina; Chiodo, Yuri; Ferrari-Amorotti, Giovanna et al. (2012) Phosphorylation of serine 21 modulates the proliferation inhibitory more than the differentiation inducing effects of C/EBPÎ± in K562 cells. J Cell Biochem 113:1704-13|
|Calabretta, Bruno; Salomoni, Paolo (2011) Inhibition of autophagy: a new strategy to enhance sensitivity of chronic myeloid leukemia stem cells to tyrosine kinase inhibitors. Leuk Lymphoma 52 Suppl 1:54-9|
|Ferrari-Amorotti, Giovanna; Mariani, Samanta Antonella; Novi, Chiara et al. (2010) The biological effects of C/EBPalpha in K562 cells depend on the potency of the N-terminal regulatory region, not on specificity of the DNA binding domain. J Biol Chem 285:30837-50|
Showing the most recent 10 out of 21 publications