Deciphering the mechanistic basis of minimal residual disease and treatment resistance in acute myeloid leukemia

Descripción del proyecto

Células madre leucémicas como impulsoras de la enfermedad

Las células madre leucémicas (CML) son una población poco frecuente compuesta por células leucémicas que dan origen a la leucemia y suelen ser resistentes a la quimioterapia. Como resultado, las CML se consideran responsables de la recaída de la enfermedad tras el tratamiento. El equipo del proyecto MRDAML, financiado por las Acciones Marie Skłodowska-Curie, tiene como objetivo definir el fenotipo y la función de las CML en el primer contacto médico, así como durante el tratamiento y la recaída. Los investigadores llevarán a cabo análisis transcriptómicos, genéticos y epigenéticos de CML procedentes de pacientes en diferentes estadios de la enfermedad e identificarán los principales agentes en la supervivencia y resistencia de las CML. Los resultados del proyecto mejorarán el conocimiento actual de la leucemia mieloide aguda y servirán de base para el futuro diseño de tratamientos específicos.

Objetivo

Acute myeloid leukemia (AML) is one of the most aggressive and deadliest cancers with frequent relapse. Although initial therapies eliminate most AML blast cells, rare cells with leukemic stem cell (LSC) activity can persist and likely generate minimal residual disease (MRD) to re-initiate AML. Thus, targeting resistant LSCs during MRD might provide a unique opportunity to prolong remission and prevent relapse. However, because it is notoriously challenging to identify rare LSCs present within the vast number of normal blood cells during MRD, the phenotype, plasticity, function and mechanisms of LSCs in resistance and relapse remains poorly understood.

Previous study from the Trumpp laboratory demonstrated a convergent pathway via hypermethylationn to drive initiation and progression of AML with IDH mutations or BCAT1 overexpression. However, the common and distinct mechanisms driving resistance in the two AML subtypes has not been explored, despite the observation that BCAT1 expression is upregulated in LSCs and upon relapse.

Thus, in this proposal, I will first perform systematic phenotypic characterization of IDHmut/BCAT1hi AML cells to develop a high-quality LSC enrichment strategy. Subsequently, I will combine cutting edge single-cell multi-omics technologies to deeply characterize the mutational, transcriptomic and epigenetic dynamics of individual LSCs at diagnosis, MRD-positive remission and relapse. State of the art analytical methods will be used to integrate these data to dissect IDHmut/BCAT1hi AML with unprecedented resolution, examine the contribution of LSCs in MRD, and identify molecular regulators mediating LSC survival and resistance. Functional validation using pharmacological intervention, genomic editing in cell lines and patient-derived xenograft models will be performed to uncover causal relationships of the identified regulators. Overall, this work will lead to better mechanistic insight of MRD and therapy resistance in IDHmut/BCAT1hi AML.