B cell acute lymphoblastic leukemias (B-ALL) are currently treated with chemotherapy with a relatively high success rate. However, chemotherapy causes long-lasting sequellae particularly in pediatric populations. In the elderly, chemotherapy is often insufficient for eliminating B-ALL, leaving these patients without therapeutic alternatives. Therefore, the pursuit for new targets and therapeutic strategies must go on to face the needs of particularly sensitive populations of patients. The most prevalent form of B-ALL is the Philadelphia chromosome preB ALL. Over the past 2 years we have been studying the crosstalk between developing B lymphocytes and a rare but physiologically critical population of stromal cells in the bone marrow known as mesenchymal progenitor cells (MPCs) that produce Interleukin-7 (IL-7). In a recently published study we described two cell circuits formed between proB and MPCs, and between preB cells and MPCs, that regulate early stages of B cell development. These findings led us to an unexpected discovery that pre- leukemic preB cells and Philadelphia chromosome preB-ALL cells physically interact with MPCs and turn-off IL-7 production by MPCs in bone marrow. In recent and unpublished studies we identified the lymphotoxin LTa1b2 ligand expressed on pre-leukemic and leukemic preB cells and the lymphotoxin beta receptor (LTbR) expressed on MPCs as the molecular mechanism that controls IL-7 production by MPCs. Importantly, turning- off the development of non-leukemic B-lineage cells results in accelerated growth of preB-ALLs, suggesting that both cell types compete for limiting factor(s). Remarkably, our preliminary studies revealed that preB-ALL cells and non-leukemic B cell progenitors are highly dependent on the anabolic nutrient Glutamine for cell proliferation/growth. Combined, our unpublished findings led us to the main hypotheses of this grant: 1- that therapeutic targeting of LTbR signaling in MPCs alters the bone marrow microenvironment and reduces preB- ALL cell growth; and 2- that preB-ALL cells compete with non-leukemic ?normal B cell progenitors? for limiting amounts of Glutamine in the bone marrow microenvironment. These hypotheses will be tested in two related but independent aims.
In aim 1, we will test the impact of LTbR signaling in bone marrow MPCs in slowing down the growth of preB-ALLs in vivo. We will use a combination of genetically modified mouse models with LTbR blocking reagents to determine if by altering IL-7 production preB-ALL growth is reduced to an extent that allows for T cell-mediated clearance of allogeneic preB-ALLs in vivo.
In Aim 2, we will explore the therapeutic potential of the Glutamine analog 6-Diazo-5-oxo-L-norleucine, a potent antagonist of Glutamine metabolism, in preventing preB-ALL cell proliferation in vivo. Success in these aims may have a major impact on the treatment of B-ALL and open new therapeutic strategies for the treatment of other blood cancers.
Defects in B cell development are major causes of immunological diseases. By investigating where and how pre-leukemic and leukemic B-lineage cells interact within bone marrow we may develop new therapeutic strategies against devastating acute lymphoblastic leukemias.