Acquired drug resistance (DR) largely limits the effectiveness of targeted cancer therapies, especially for
aggressive diseases, such as mantle cell lymphoma (MCL), a B-cell lymphoma with poor prognosis. Recently,
FDA approved drug Venetoclax (ABT-199), a novel, potent and selective small-molecule BCL-2 inhibitor was
clinically vetted as an effective therapy for hematopoietic tumors, including MCL. The use of ABT-199
produced a dramatic response; however, the emergence of resistance to this drug was ensued by fatal
progression of the MCL. Once MCL patients relapse from ABT-199 treatment, either during or after, there is
rapid disease progression and accelerated mortality. Thus, there is an urgent need to define mechanisms of
ABT-199 resistance (AR) and identify targets to bring forward novel treatment options with tangible curative
potential. We modeled drug resistance to ABT-199 by generating AR cell lines from MCL, and characterized
the adaptive molecular reprogramming to ABT-199 treatment in these cells. Small subpopulations of lymphoma
cells were consistently detected that evade strong selective ABT-199 pressure by entering a reversible drug
tolerant 'persister' state (DTP), and consequently leading to a DTP expansion population (DTEP) and eventual
acquisition of bona fide drug resistance. Given the premise that a myriad of mechanisms are involved in MCL
AR, we applied network-wide, robust and unbiased approaches to determine the major altered MCL signaling
pathways during AR evolution. More complex and more dynamic than we had anticipated, we observed that
these DTEP cells conferred increased viability and clonogenic growth, associated with BH3 family protein
reprogramming. Intriguingly, DTEP cells can revert back to drug sensitive states after long-term passaging
without the drug, supporting the notion that these cells are epigenetically reprogrammed to drug resistant
states. Consistent with these results, our initial drug screen revealed the exquisite sensitivity to epigenetic
machinery inhibitors (e.g., BRD4, CDK7) in ABT-199 DTEP cells when compared with parental cells. In line
with this, our immunoprecipitation-sequencing (ChIP-Seq) and RNA-Seq assays revealed dynamic super
enhancer (SE) remodeling in DTEP MCL cells, and this chromatin alteration is associated with CDK7-mediated
transcription in ABT-199 resistant MCL cells. We propose that transcriptional and epigenetic adaptive
responses are required for the survival of cells that persist in the presence of ABT-199 therapy. The objective
of this proposal is to strategically target transcriptional machinery and provide pre-clinical validation by
targeting CDK7/BRD4, in combination with BCL-2 as an efficient and durable treatment for MCL. With the
small molecule tools for epigenetic targets and patient-derived xenograft (PDX) model available in the Qi and
Tao laboratories, respective expertise and the unique access to a large resource of primary MCL samples, the
study allows us to gain valuable insights into MCL drug resistance biology and uncover a novel mechanism-
driven therapy for MCL patients.