Investigating therapy-induced leukemia stem cell rewiring

• Applicant: Professorin Dr. Claudia Lengerke
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566352518

WIDER RESEARCH CONTEXT: Cancer cell populations are heterogenous, and outgrowth of therapy-persistent subpopulations underlies re-progression. Acute myeloid leukemia (AML) exhibits high intrapatient heterogeneity among leukemic cells with subpopulations of leukemic stem cells (LSCs) essential for both leukemia induction and therapy resistance. Moreover, therapy-induced senescence was shown to enforce reprogramming of non-LSCs into LSCs. We previously found LSCs to selectively evade NK cell recognition, and treatment with PARP1 inhibitors or hypomethylating agents (HMA) to resensitize LSCs (and AML cells, respectively) to NK cell attack. HYPOTHESIS: “One-two-punch” concepts may overcome cancer cell persistence. We hypothesized that an early switch from chemotherapeutic induction to HMA and the Bcl2 blocker venetoclax (Ven) as bridging to allo-transplant may inhibit the outgrowth of therapy-resistant LSCs. Cell state-focused longitudinal studies of LSCs in their bone marrow (BM) niche will unveil mechanisms of persistence and novel vulnerabilities that can be exploited to better target LSCs. APPROACH: Recruitment into our “VenSwitch” trial started in October 2023. Patients with persisting cancer cells at day 14 after induction chemotherapy are switched to HMA/Ven to improve LSC clearance and prevent disease persistence. Using material form this trial, we will longitudinally explore the molecular makeup and cellular states of individual leukemia and immune (NK cell)- ecosystems at initial diagnosis, after chemo-induction, following HMA/ Ven, and, if occurring, in relapse samples. Furthermore, as part of this project we will perform analyses of cellular senescence as a pivotal state switch associated with LSC persistence or de novo LSC formation. Next to flow-phenotypic and single-cell (sc)RNA-seq-based analyses, we will perform antibody-based spatial sc-CODEX and MACSima analyses to scrutinize the BM as a persister-supportive niche, and convert unveiled cellintrinsic and microenvironmental vulnerabilities into novel combinatorial treatments. Preventing LSC persister outgrowth to facilitate AML cure will be further validated in PDX models cotransplanted with human immune cells. LEVEL OF ORIGINALITY: Comprehensive longitudinal exploration of AML cells with innovative zooming into cellular state switches, cellular neighborhoods and their dynamic immunogenicity in persistent leukemias.

• DFG Programme: Research Grants