Abstract
Simple SummaryRisk-adapted multiagent chemotherapy has led to a remarkable improvement in the life expectancy of patients with acute lymphoblastic leukemia (ALL). Nevertheless, in high-risk subgroups such as BCR-ABL+ ALL, relapse rates remain high without allogeneic hematopoietic stem cell transplantation, and the adverse effects of chemotherapy may cause acute and chronic cardiac complications or dysfunction. Here, we demonstrated that chemotherapy-free targeted therapies designed to optimize apoptosis induction in BCR-ABL+ ALL may circumvent cardiac on-target side effects and may even activate cardiac recovery.Targeted therapies are currently considered the best cost–benefit anti-cancer treatment. In hematological malignancies, however, relapse rates and non-hematopoietic side effects including cardiotoxicity remain high. Here, we describe significant heart damage due to advanced acute lymphoblastic leukemia (ALL) with t(9;22) encoding the bcr-abl oncogene (BCR-ABL+ ALL) in murine xenotransplantation models. Echocardiography reveals severe cardiac dysfunction with impaired left ventricular function and reduced heart and cardiomyocyte dimensions associated with increased apoptosis. This cardiac damage is fully reversible, but cardiac recovery depends on the therapy used to induce ALL remission. Chemotherapy-free combination therapy with dasatinib (DAS), venetoclax (VEN) (targeting the BCR-ABL oncoprotein and mitochondrial B-cell CLL/Lymphoma 2 (BCL2), respectively), and dexamethasone (DEX) can fully revert cardiac defects, whereas the depletion of otherwise identical ALL in a genetic model using herpes simplex virus type 1 thymidine kinase (HSV-TK) cannot. Mechanistically, dexamethasone induces a pro-apoptotic BCL2-interacting mediator of cell death (BIM) expression and apoptosis in ALL cells but enhances pro-survival B-cell lymphoma extra-large (BCLXL) expression in cardiomyocytes and clinical recovery with the reversion of cardiac atrophy. These data demonstrate that therapies designed to optimize apoptosis induction in ALL may circumvent cardiac on-target side effects and may even activate cardiac recovery. In the future, combining the careful clinical monitoring of cardiotoxicity in leukemic patients with the further characterization of organ-specific side effects and signaling pathways activated by malignancy and/or anti-tumor therapies seems reasonable.
Highlights
Acute lymphoblastic leukemia (ALL) is a heterogeneous cancer disease of lymphoid blood cells, characterized by the accumulation of large numbers of immature lymphocytes, often harboring multiple genetic aberrations
We used the previously described BCR-ABL+ acute lymphoblastic leukemia (ALL) cell line BV173 and patient-derived ALL xenografts (PDX) with stable luciferase expression, which allows noninvasive bioluminescence imaging (BLI) to be used to visualize the leukemic burden in NSG mice (Figures 1a and S1a) [9]
Female NSG mice systemically engrafted with BV173 cells developed aggressive leukemia with a mean survival of 32 ± 2 days [9,10] (Figure 1a)
Summary
Acute lymphoblastic leukemia (ALL) is a heterogeneous cancer disease of lymphoid blood cells, characterized by the accumulation of large numbers of immature lymphocytes, often harboring multiple genetic aberrations. The Philadelphia translocation t(9;22)(q34;q11) defines a very high-risk subtype of B cell precursor (BCP) ALL [1,2,3]. The resulting chimeric fusion protein BCR-ABL has constitutive tyrosine kinase activity that is essential for malignant transformation. The targeted inhibition of BCR-ABL tyrosine kinase activity by tyrosine kinase inhibitors (TKI), such as dasatinib (DAS) induction and post-remission chemotherapy regimens, has markedly improved patient outcomes for this high-risk subgroup [3,4]. The combination of TKI with known cardiotoxic anti-cancer drugs such as anthracyclines is not recommended
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