Chemotherapy-Responsive Acute Myeloid Leukemia in a Veiled Chameleon (Chamaeleo calyptratus)

A 4-year-old captive-bred male veiled chameleon (Chamaeleo calyptratus) presented with anorexia, weight loss, and stomatitis. Complete blood count revealed pancytopenia and a marked leukocytosis (197 x103/µL) composed of blast cells (195 x103/µL) that had oval to irregular nuclei with finely stippled chromatin and occasional nucleoli. The diagnosis was acute leukemia of presumptive myeloid origin. Treatment with prednisone (1.5 mg/kg once daily orally) and cytosine arabinoside (300 mg/m2 subcutaneously) was initiated. Post-treatment hematologic analysis revealed decreased blast count (88.5 x103/µL) and improved mentation. Additional doses of cytosine arabinoside were given two and three weeks after the initial diagnosis with marked improvement in circulating blast concentration (15.3 x103/µL). During the course of treatment, which included the chemotherapeutics, fluid therapy, and oral supportive care, the chameleon’s weight increased 32.5% (199 g to 295 g). Unfortunately, the animal died 33 days after presentation. Histopathologic evaluation revealed hypocellular bone marrow with rare blast-like cells within vessels and mycotic granulomatous hepatitis with intralesional hyphae and fructiferous bodies. The blast cells expressed Iba1 but not CD3, CD79a, or lysozyme, suggesting a myeloid origin. Cell morphology further reinforced an acute myeloid leukemia. The authors surmised that the chameleon was responding to treatment, but ultimately succumbed to the mycotic hepatitis. This report describes the first case of acute myeloid leukemia with response to chemotherapeutic intervention in a veiled chameleon.

Downregulation of MTSS1 in acute myeloid leukemia is associated with a poor prognosis, chemotherapy resistance, and disease aggressiveness

Despite recent approval of targeted drugs for acute myeloid leukemia (AML) therapy, chemotherapy with cytosine arabinoside and anthracyclines remains an important pillar of treatment. Both primary and secondary resistance are frequent and associated with poor survival, yet the underlying molecular mechanisms are incompletely understood. In previous work, we identified genes deregulated between diagnosis and relapse of AML, corresponding to therapy naïve and resistant states, respectively. Among them was MTSS1, whose downregulation is known to enhance aggressiveness of solid tumors. Here we show that low MTSS1 expression at diagnosis was associated with a poor prognosis in AML. MTSS1 expression was regulated by promoter methylation, and reduced by cytosine arabinoside and the anthracycline daunorubicin. Experimental downregulation of MTSS1 affected the expression of numerous genes. It induced the DNA damage response kinase WEE1, and rendered human AML cell lines more resistant to cytosine arabinoside, daunorubicin, and other anti-cancer drugs. Mtss1 knockdown in murine MLL-AF9-driven AML substantially decreased disease latency, and increased leukemic burden and ex vivo chemotherapy resistance. In summary, low MTSS1 expression represents a novel factor contributing to disease aggressiveness, therapy resistance, and poor outcome in AML.

Epigenetic suppression of SLFN11 in germinal center B-cells during B-cell development

Background SLFN11 has recently been reported to execute cancer cells harboring replicative stress induced by DNA damaging agents. However, the roles of SLFN11 under physiological conditions remain poorly understood. Germinal center B-cells (GCBs) undergo somatic hypermutations and class-switch recombination, which can cause physiological genotoxic stress. Hence, we tested whether SLFN11 expression needs to be suppressed in GCBs during B-cell development. Objective To clarify the expression profile of SLFN11 in different developmental stages of B-cells and B-cell-derived cancers. Methods We analyzed the expression of SLFN11 by mining cell line databases for different stages of normal B-cells and various types of B-cell-derived cancer cell lines. We performed dual immunohistochemical staining for SLFN11 and B-cell specific markers in normal human lymphatic tissues. We tested the effects of two epigenetic modifiers, an EZH2 inhibitor, tazemetostat (EPZ6438) and a histone deacetylase inhibitor, panobinostat (LBH589) on SLFN11 expression in GCB-derived lymphoma cell lines. We also examined the therapeutic efficacy of these drugs in combination with cytosine arabinoside and the effects of SLFN11 on the efficacy of cytosine arabinoside in SLFN11-overexpressing cells. Results SLFN11 mRNA level was found low in both normal GCBs and GCB-DLBCL (GCB like-diffuse large B-cell lymphoma). Immunohistochemical staining showed low SLFN11 expression in GCBs and high SLFN11 expression in plasmablasts and plasmacytes. The EZH2 and HDAC epigenetic modifiers upregulated SLFN11 expression in GCB-derived lymphoma cells and made them more susceptible to cytosine arabinoside. SLFN11 overexpression further sensitized GCB-derived lymphoma cells to cytosine arabinoside. Conclusions The expression of SLFN11 is epigenetically suppressed in normal GCBs and GCB-derived lymphomas. GCB-derived lymphomas with low SLFN11 expression can be treated by the combination of epigenetic modifiers and cytosine arabinoside.