Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the presence of somatic mutations in hematopoietic cells of an individual who does not have a blood cancer by clinicopathologic criteria. The prevalence of CHIP increases with aging: 10% of adults >60 years and 20-30% of adults >70 years were found to carry at least one CHIP clone. Therefore, the term ARCH (age-related clonal hematopoiesis) is often used to highlight that CHIP is a marker of hematopoietic cell aging. Individuals who carry CHIP mutations have 11-times higher risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) compared to the age-matched population without ARCH. Saygin Lab has also shown that ARCH is a risk factor for acute lymphoblastic leukemia (ALL) in older adults. Mechanisms by which ARCH drives MDS/AML vs ALL are not fully elucidated, and this is an area of active research in our laboratory. Our long-term goal is to develop new interventions to prevent blood cancers before they arise from these high-risk precursor conditions.

Therapy-related myeloid neoplasms (t-MNs) are well-established long-term complications observed in patients treated with chemo- and/or radiotherapy for a primary cancer, or an autoimmune disorder. Recent advances in deep sequencing techniques have shed light on the pathogenesis of t-MNs, identifying CHIP as a frequent first step in the multi-hit model of leukemogenesis. CHIP clones are often detectable prior to any genotoxic therapy, setting the stage for secondary somatic mutations to accumulate. We and others have previously shown that the evolution towards t-MN is shaped by the type of chemotherapy, the aging process, and individual exposures. While most patients who develop leukemia after prior genotoxic therapy will present with t-MN, a rare subset may develop therapy-related ALL. We have recently characterized this entity, which constitutes 5-7% of adult ALL cases and harbors high-risk genetic changes such as hypodiploidy and TP53 mutations. The prevalence of therapy-related ALL has been increasing with the widespread use of lenalidomide maintenance for multiple myeloma, as well as the improvement in the survival of patients with solid tumors. Leveraging laboratory models of therapy-related leukemia and serial samples obtained from patients treated at the University of Chicago, we aim to understand how these diseases evolve so that we can develop risk stratification models and new therapies for high-risk individuals.

Relapsed/refractory T-ALL has very poor prognosis due to the paucity of available drugs for this disease. A new class of drug has not been FDA-approved for over a decade. In Saygin Lab, we focus on new experimental therapeutics for high-risk T-ALL. This includes BH3 mimetics, which are drugs that work by activating suicide pathways (apoptosis) in leukemia cells. We showed that dual targeting of BCL-2 and BCL-xL antiapoptotic proteins has remarkable activity against both newly diagnosed and relapsed T-ALL patient cells, as well as animal models of T-ALL. We further discovered that LCK and ACK1 signaling pathways drive treatment resistance, and the combination of tyrosine kinase inhibitors (dasatinib or ponatinib) plus BCL-2/BCL-xL dual inhibitors (NWP-0476) has robust synergistic anti-leukemic effect. Based on these promising preclinical data, we have launched a new phase 1b/2 clinical trial program that is funded by Leukemia Lymphoma Society Academic Clinical Trials Award, and will offer this combination therapy to high-risk T-ALL patients.

In addition to the discovery science and translational research summarized above, Saygin Lab also supports clinical trials by biobanking human samples and conducting several correlative studies such as BH3 profiling, measurable residual disease (MRD) analysis by ASO-qPCR or V(D)J next generation sequencing (NGS)-based assays, DNA and RNA sequencing analyses of samples to understand patterns of response and mechanisms of resistance to novel therapeutics. Our expertise in correlative science enables us to achieve the full circle of bench-to-bedside and bedside-to-bench research.