Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with the T-cell subtype, T-ALL, representing ~15% of cases. Although aggressive chemotherapy regimens have improved 5-year survival rates to over 90%, these therapies often result in lifelong morbidities. Also, patients who fail to respond to chemotherapy or who relapse have dismal outcomes. Therefore, there is an unmet clinical need to develop alternative therapies for T-ALL. Despite harboring leukemia-promoting mutations, T-ALL cells do not survive alone, but require signals from the tumor microenvironment (TME) to thrive. We found that myeloid cells from multiple leukemic organs support growth of mouse and human T-ALL...

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Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with the T-cell subtype, T-ALL, representing ~15% of cases. Although aggressive chemotherapy regimens have improved 5-year survival rates to over 90%, these therapies often result in lifelong morbidities. Also, patients who fail to respond to chemotherapy or who relapse have dismal outcomes. Therefore, there is an unmet clinical need to develop alternative therapies for T-ALL. Despite harboring leukemia-promoting mutations, T-ALL cells do not survive alone, but require signals from the tumor microenvironment (TME) to thrive. We found that myeloid cells from multiple leukemic organs support growth of mouse and human T-ALL cells, implicating them as promising therapeutic targets. Myeloid cells are heterogeneous, and they become altered in the presence of T-ALL, enhancing their ability to support leukemia growth. In Aim 1, we will identify myeloid subsets required for T-ALL progression in multiple organs. Two distinct T-ALL subtypes will be studied as our preliminary data show that both are supported by myeloid cells, but through distinct mechanisms. We will test the function of candidate myeloid subsets identified previously, and we will carry out single-cell transcriptional profiling and multiplex imaging to comprehensively assess how T-ALL alters the cellular composition, molecular profile, and organization of myeloid cells to support leukemia progression. In Aim 2, we will test the hypothesis that myeloid cells support distinct T-ALL subtypes via different signals that metabolically rewire T-ALL, and we will test if targeting myeloid-mediated support treats refractory disease. Altogether, this project will comprehensively identify myeloid cells and signals that support T-ALL in distinct organs, including the CNS, a site associated with inferior prognosis. Our overall goal is to identify promising therapeutic targets in the TME that can be developed to improve pediatric T-ALL patient outcomes.

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