CALCRL Targeting Eradicates Chemoresistant Leukemic Stem Cells
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for acute myeloid leukemia (AML) often fail to eradicate chemoresistant leukemic stem cells, leading to frequent relapses due to the persistence of drug-resistant stem cell populations, which are challenging to distinguish from normal hematopoietic stem cells.
Innovation Solution
Targeting the adrenomedullin receptor CALCRL, which is overexpressed in AML patients, particularly in the immature CD34+ CD38− compartment, using antibodies or inhibitors to deplete leukemic stem cells, thereby sensitizing them to chemotherapy and overcoming relapse.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional chemotherapy is used to treat AML, then chemosensitive leukemic cells are eradicated, but chemoresistant leukemic stem cells persist and cause relapse
Solution Approach 1:
The invention segments the leukemic cell population by identifying distinct phenotypic markers (CD34+, CD38-, TIM-3+, CD47+) that differentiate chemoresistant leukemic stem cells from chemosensitive leukemic cells and normal hematopoietic stem cells. This segmentation enables targeted therapy that specifically eliminates the chemoresistant subset while preserving normal stem cells, thereby preventing relapse without compromising the eradication of leukemic cells.
Solution Approach 2:
The invention applies local quality by developing targeted therapies (such as anti-CD47 antibodies or BCL-2 inhibitors) that specifically act on chemoresistant leukemic stem cells expressing particular markers, rather than applying uniform chemotherapy to all cells. This localized approach ensures that the therapeutic action is concentrated on the problematic chemoresistant population while sparing other cell types.
2Reliability
If targeted therapy against specific markers is used to eradicate leukemic stem cells, then relapse is prevented, but normal hematopoietic stem cells may be harmed
Solution Approach 1:
The invention exploits asymmetry in marker expression patterns between leukemic and normal stem cells. Normal hematopoietic stem cells are typically CD34+CD38-, but they lack the co-expression of TIM-3 and CD47 markers that characterize chemoresistant leukemic stem cells. This asymmetric marker profile allows therapies targeting the combination of these markers to selectively eliminate leukemic cells while preserving normal stem cells.
Solution Approach 2:
The invention uses specific molecular markers (TIM-3, CD47, BCL-2) as intermediaries that are overexpressed or uniquely expressed in chemoresistant leukemic stem cells. These intermediaries serve as targets for therapeutic agents, enabling selective destruction of leukemic cells through antibody-mediated or inhibitor-mediated mechanisms that do not affect normal stem cells lacking these intermediaries.
3Productivity
If chemotherapy is intensified to eliminate all leukemic cells, then complete remission is achieved, but toxicity to normal cells increases
Solution Approach 1:
The invention extracts or isolates the chemoresistant leukemic stem cell population based on their unique phenotypic characteristics (CD34+CD38-TIM-3+CD47+). By identifying and targeting this specific subset through marker-based selection, the therapy can eliminate the source of relapse without requiring intensive chemotherapy that would damage normal cells, thereby achieving complete remission with reduced toxicity.
Data Source
AI summary
After intensive chemotherapy, the emergence of cells with dmg resistant and/or stem cell features might explain frequent relapses and the poor outcome of patients with acute myeloid leukemia (AML). Herein the inventors first uncovered that the adrenomedullin receptor CALCRL is overexpressed in AML patients comparing with normal cells and preferentially in the immature CD34+ CD38− compartment. Then they demonstrated its role in the maintenance of leukemic stem cell function in vivo. Moreover, CALCRL depletion strongly affected leukemic growth in xenograft models and sensitized to chemotherapeutic agent cytarabine in vivo. It Accordingly, the inventors showed that ADM-CALCRL axis drove cell cycle, DNA integrity, and high OxPHOS status of chemoresistant AML stem cells in an E2F1- and BCL2-dependent manner. Furthermore, CALCRL depletion sensitizes cells to cytarabine and its CT expression predicted the response to chemotherapy in vivo in mice. Further, using the combination of limiting dilution assays, single-cell RNA-seq analysis of primary AMF samples at diagnosis and relapse and before and after transplantation in NSG mice, the inventors revealed the pre-existence of a chemoresistant leukemic stem cell sub-population harboring a CALCRL-driven gene signature. Finally the inventors strongly demonstrated that chemoresistant LSC are dependent for CALCRL. All of these data highlight the critical role of CALCRL in stem cell survival, proliferation and metabolism and identify this receptor as a new marker of chemoresistant leukemic stem cell population and a promising therapeutic target to specifically eradicate them and overcome relapse in AML.