A degradation-resistant c-Myb mutant cooperates with Bcl-2 in enhancing proliferative potential and survival of hematopoietic cells

Corradini, Francesca; Bussolari, Rita; Cerioli, D.; Lidonnici, Maria Rosa; Calabretta, Bruno

doi:10.1016/j.bcmd.2007.06.002

Cited by 5 publications

(6 citation statements)

References 22 publications

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“…We also investigated the requirement of MYB in NSG mice injected with shMYB-transduced patient-derived Ph+ ALL cells (ALL-674). For this experiment, transduced cells (approximately 10% GFP-positive) were expanded in a recipient NSG mouse, GFP-sorted from the bone marrow and injected in female NSG recipient mice to obtain a more efficient engraftment (33). Leukemia progression was monitored by periodic analysis of total leukemic (CD19+) or shMYB-transduced (GFP+) cells.…”

Section: Resultsmentioning

confidence: 99%

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Targeting CDK6 and BCL2 Exploits the “MYB Addiction” of Ph+ Acute Lymphoblastic Leukemia

et al. 2018

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Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) is currently treated with BCR-ABL1 tyrosine kinase inhibitors (TKI) in combination with chemotherapy. However, most patients develop resistance to TKI through BCR-ABL1-dependent and -independent mechanisms. Newly developed TKI can target Ph ALL cells with BCR-ABL1-dependent resistance; however, overcoming BCR-ABL1-independent mechanisms of resistance remains challenging because transcription factors, which are difficult to inhibit, are often involved. We show here that (i) the growth of Ph ALL cell lines and primary cells is highly dependent on MYB-mediated transcriptional upregulation of CDK6, cyclin D3, and BCL2, and (ii) restoring their expression in MYB-silenced Ph ALL cells rescues their impaired proliferation and survival. Levels of MYB and CDK6 were highly correlated in adult Ph ALL ( = 0.00008). Moreover, Ph ALL cells exhibited a specific requirement for CDK6 but not CDK4 expression, most likely because, in these cells, CDK6 was predominantly localized in the nucleus, whereas CDK4 was almost exclusively cytoplasmic. Consistent with their essential role in Ph ALL, pharmacologic inhibition of CDK6 and BCL2 markedly suppressed proliferation, colony formation, and survival of Ph ALL cells and in mice. In summary, these findings provide a proof-of-principle, rational strategy to target the MYB "addiction" of Ph ALL. MYB blockade can suppress Philadelphia chromosome-positive leukemia in mice, suggesting that this therapeutic strategy may be useful in patients who develop resistance to imatinib and other TKIs used to treat this disease. .

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Section: Resultsmentioning

confidence: 99%

“…The E308G mutation was introduced by a similar method. The pLXSP-BCL2 retrovirus was previously described (33). Lentiviral or retroviral VSV-G pseudo-typed particles were produced by calcium phosphate transfection of plasmid vectors into HEK-293T cells in combination with helper plasmids.…”

Section: Methodsmentioning

confidence: 99%

Targeting CDK6 and BCL2 Exploits the “MYB Addiction” of Ph+ Acute Lymphoblastic Leukemia

et al. 2018

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“…Imatinib-resistant BCR/ABL-positive KCL22/SR CML cells exhibited suppressed MYB levels in contrast to cells of the sensitive parent cell line [126] . However, MYB has a longer PI3K-signaling-dependent half-life in BCR/ABL-expressing cells than in normal cells, and the presence of degradation-resistant MYB mutants in transfected CML cells conveyed resistance to imatinib-mediated apoptosis independent from the MYB expression level [127] . The anti-apoptotic effect of the degradation-resistant MYB mutant was enhanced by co-expression of BCL2 [128] .…”

Section: Resistance To Targeted Therapymentioning

confidence: 99%

“…The PI3K inhibitor LY294002 downregulated MYB in parent and BCR/ABL-positive murine IL3-dependent 32Dcl3 myeloid precursor cells by reducing MYB stability and promoting MYB degradation, which has the potential to overcome imatinib resistance [127] . The cytotoxicity of the Ras-mimetic PI3K/PLK1 inhibitor rigosertib in diffuse large B-cell lymphoma (DLBCL) cells was associated with MYB suppression and inhibition of nuclear MYB translocation by sumoylation.…”

Section: Kinase Inhibitorsmentioning

confidence: 99%

Emerging role of MYB transcription factors in cancer drug resistance

Biersack,

Höpfner

2024

Cancer Drug Resist

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Decades ago, the viral myeloblastosis oncogene v -myb was identified as a gene responsible for the development of avian leukemia. However, the relevance of MYB proteins for human cancer diseases, in particular for solid tumors, remained basically unrecognized for a very long time. The human family of MYB transcription factors comprises MYB (c-MYB), MYBL2 (b-MYB), and MYBL1 (a-MYB), which are overexpressed in several cancers and are associated with cancer progression and resistance to anticancer drugs. In addition to overexpression, the presence of activated MYB-fusion proteins as tumor drivers was described in certain cancers. The identification of anticancer drug resistance mediated by MYB proteins and their underlying mechanisms are of great importance in understanding failures of current therapies and establishing new and more efficient therapy regimens. In addition, new drug candidates targeting MYB transcription factor activity and signaling have emerged as a promising class of potential anticancer therapeutics that could tackle MYB-dependent drug-resistant cancers in a more selective way. This review describes the correlation of MYB transcription factors with the formation and persistence of cancer resistance to various approved and investigational anticancer drugs.

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“…The main product of the c-myb gene is a 75KDa nuclear protein that contains three functional domains: (i) an N-terminal DNA-binding domain that specifically binds to the sequence PyAACG/TG; (ii) a centrally-located transcription activation domain; and (iii) a C-terminal negative regulatory domain (NRD), which includes a leucine zipper and an EVES motif that modulate the activity of c-Myb via inter-and intra-molecular interactions. 29 , 30 …”

Section: Introductionmentioning

confidence: 99%

Expression of p89c-Mybex9b, an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells

Manzotti

Mariani

Corradini

et al. 2012

Blood Cancer Journal

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The c-Myb gene encodes the p75c-Myb isoform and less-abundant proteins generated by alternatively spliced transcripts. Among these, the best known is pc-Mybex9b, which contains 121 additional amino acids between exon 9 and 10, in a domain involved in protein–protein interactions and negative regulation. In hematopoietic cells, expression of pc-Mybex9b accounts for 10–15% of total c-Myb; these levels may be biologically relevant because modest changes in c-Myb expression affects proliferation and survival of leukemic cells and lineage choice and frequency of normal hematopoietic progenitors. In this study, we assessed biochemical activities of pc-Mybex9b and the consequences of perturbing its expression in K562 and primary chronic myeloid leukemia (CML) progenitor cells. Compared with p75c-Myb, pc-Mybex9b is more stable and more effective in transactivating Myb-regulated promoters. Ectopic expression of pc-Mybex9b enhanced proliferation and colony formation and reduced imatinib (IM) sensitivity of K562 cells; conversely, specific downregulation of pc-Mybex9b reduced proliferation and colony formation, enhanced IM sensitivity of K562 cells and markedly suppressed colony formation of CML CD34+ cells, without affecting the levels of p75c-Myb. Together, these studies indicate that expression of the low-abundance pc-Mybex9b isoform has an important role for the overall biological effects of c-Myb in BCR/ABL-transformed cells.

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A degradation-resistant c-Myb mutant cooperates with Bcl-2 in enhancing proliferative potential and survival of hematopoietic cells

Cited by 5 publications

References 22 publications

Targeting CDK6 and BCL2 Exploits the “MYB Addiction” of Ph+ Acute Lymphoblastic Leukemia

Targeting CDK6 and BCL2 Exploits the “MYB Addiction” of Ph+ Acute Lymphoblastic Leukemia

Emerging role of MYB transcription factors in cancer drug resistance

Expression of p89c-Mybex9b, an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells

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