|Category||Advanced Practice Professional||Job type||Full Time|
A position of Senior Research Investigator is open to investigate the role of the cell cycle regulatory protein CDK6 in Philadelphia-positive acute lymhoblastic leukemia (Ph+ ALL) and Ph1-like B-ALL. These ALL subtypes account for most cases of "high-risk" adult B-ALL. Current therapies with tyrosine kinase inhibitors (TKIs) have improved the outcome of Ph+ ALL, but resistance to TKIs develops rapidly in most patients. Ph1-like B-ALL is currently treated with standard chemotherapy but clinical responses are short-lived. Our preliminary studies indicate that CDK6 silencing is more effective than CDK6 enzymatic inhibition in suppressing Ph+ ALL in mice, suggesting that kinase-independent effects are important for the requirement of CDK6 by B-ALL cells. To block kinase-dependent and independent effects of CDK6, we have developed CDK4/6-targeted proteolysis-targeting chimera (PROTACs) that inhibit CDK4/6 enzymatic activity in vitro and promote the preferential degradation of CDK6 over CDK4 in Ph+ and Ph1-like ALL cells, providing durable suppression of CDK6 function. The individual who is chosen for the position will assess the requirement of CDK6 in Ph+ and Ph1-like ALL by comparing the effects of CDK6 degradation by CDK6-targeted proteolysis-targeting chimeras (PROTACs) and pharmacological inhibition using Palbociclib, an FDA-approved CDK4/6 inhibitor (Task1). He/she will also investigate whether the more potent leukemia suppression induced by CDK6 down-regulation in comparison to CDK6 enzymatic inhibition can be explained by changes in gene expression induced selectively by CDK6 silencing. In particular, genes to be investigated include the histone deacetylase 1(HDAC1) gene, genes involved in mitochondrial metabolic pathways, and novel CDK6-regulated genes identified by other genome-wide approaches,(Task 2).
Expertise is required in basic techniques in molecular and cellular biology and in mouse studies to assess the therapeutic effects of novel anti-leukemia agents.
Publications associated with project:
1. De Dominici M. et al. Targeting CDK6 and BCL2 Exploits the "MYB Addiction" of Ph + Acute
Lymphoblastic Leukemia . Cancer Res 78: 1097-1109, 2018. PMID: 29233926.
2. De Dominici M. et al. Selective inhibition of Ph-positive ALL cell growth through kinase-dependent
and -independent effects by CDK6-specific PROTACs. Blood 135: 1560-1573, 2020. PMID: 32040545.
MD/PhD degree, 5+ years managing labs
Jefferson Health delivers state of the art healthcare services to patients throughout the Delaware Valley and southern New Jersey. Jefferson (Philadelphia University + Thomas Jefferson University) provides more than 8,400 students from nearly 40 states and 40 countries with 21st century professional education. Combined, we have over 30,000 employees.
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|Employer||Abington Hospital - Jefferson Health|