Principle Investigator: Jose Cancelas Perez, MD, PhD
Precursor B-ALL, the most frequent tumor in children, arises with the acquisition of a transforming, leukemia-initiating event in hematopoietic progenitors and subsequent gene deletions at lineage specific hotspots. Chemotherapy resistant B-ALL has, even in the era of CAR-T cell immunotherapy, a 50% survival rate. The pathophysiological processes resulting in B-ALL transformation involve increased proliferation and differentiation arrest at an early stage of B-cell differentiation, selection of clonal population of lymphoid cells, and accumulation of malignant, poorly differentiated lymphoid cells within the bone marrow, peripheral blood, and extramedullary sites.
The intervention of targets required for oncogene induced B cell differentiation arrest could be novel therapeutic options in poor prognosis B-ALL subtypes. We have demonstrated that aPKCλ-RAC- MEK-ERK induced upregulation of chromatin modifier SATB2 is essential for differentiation arrest and blastic transformation of B-cell progenitors in Ph+ B-ALL, and genetic or pharmacological intervention of the upstream regulator of SATB2 led to increased differentiation and abrogation of leukemia. We continue to study the role of SATB2 in the epigenetic regulation and B-ALL development by determining the effects of leukemogenic Satb2 in in vivo lymphoid leukemogenesis and evaluating the role of SATB2 in chromatin organization and epigenetic modulation of target genes during blastic transformation of B-cell progenitors.