Dissecting molecular interplay between leukemic stem cells and their niche in acute and chronic myeloid leukemia

The main challenge for treating leukemias is therapy resistance, resulting in treatment failure and relapse, which ultimately leads to death. Consequently, there is an urgent need for more effective therapies.

Accumulating evidence suggests that drug resistance and relapse is due to the persistence of residual leukemia-initiating stem cells (LSCs) that are protected by bone marrow (BM) microenvironment, the so-called niche.

Thus, targeting the leukemia niche may offer new treatment options to sensitize to chemotherapy enabling LSC eradication to cure the diseases. However. little is known about the key niche factors contributing to LSC resistance and relapse.

This projectaims to unravel critical molecular pathways mediating LSC interactions with their niche in acute and chronic myeloid leukemia and the functional impact of the pathways on therapy response of the LSC using both patient samples and mouse models. We have identified some the candidate niche factors including Lama4 and CXCL14.

Here we will determine their therapeutic effects on the LSCs and the underlying mechanisms by RNA sequencing and metabolic assays in co-culture systems and patient-derived xenograft mouse models. CRISPR-based gene-editing or protein overexpression will be utilized to restore the candidate niche factor expression.

The project will advance our knowledge about niche regulation of the leukemias and enable us to identify key molecules that can be targeted to overcome drug resistance.