Leukemia-associated translocation products able to activate RAS modify PML and render cells sensitive to arsenic-induced apoptosis

Abstract

Since the 19th century, arsenic (As 2 O 3 ) has been used in the treatment of chronic myelogenous leukemia (CML) characterized by the t(9;22) translocation. As 2 O 3 induces complete remissions in patients with acute promyelocytic leukemia. The response to As 2 O 3 is genetically determined by the t(15;17)-or the t(9;22)-specific fusion proteins PML/RARa or BCR/ABL. The PML portion of PML/RARa is crucial for the sensitivity to As 2 O 3 . PML is nearly entirely contained in PML/RARa. PML is upregulated by oncogenic RAS in primary fibroblasts. The aberrant kinase activity of BCR/ABL leads to constitutive activation of RAS. Therefore, we hypothesized that BCR/ ABL could increase sensitivity to As 2 O 2 -induced apoptosis by modifying PML expression. To disclose the mechanism of As 2 O 3 -induced apoptosis in PML/RARaand BCR/ABL-expressing cells, we focused on the role of PML for As 2 O 3 -induced cell death. Here we report that (i) sensitivity to As 2 O 3 -induced apoptosis of U937 cells can be increased either by overexpression of PML, or by conditional expression of activated RAS; (ii) also the expression of the t(8;21)-related AML-1/ETO increased sensitivity to As 2 O 3 -induced apoptosis; (iii) both BCR/ ABL and AML-1/ETO activated RAS and modified the PML expression pattern; (iv) the expression of either BCR/ABL or AML-1/ETO rendered U937 cells sensitive to interferon a-induced apoptosis. In summary, these data suggest a crucial role of factors able to upregulate PML for As 2 O 2 -induced cell death.

All-trans retinoic acid/As 2 O 3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia

“…It may be interesting to note that the voltage-dependant anion channel (VDAC), a component of the protein complex regulating PTP, was the target of As 2 O 3 (48). The recently illustrated PML-dependent effect provides another mechanism of As 2 O 3 -induced apoptosis (49). In this study, ATRA displayed a slight apoptotic effect on APL cells in vivo and in vitro.…”

Acute promyelocytic leukemia: PML/RARα and the leukemic stem cell

“…In fact, PML-NBs are not only disrupted in cells expressing PML/RARa but are targeted also by other leukemia-defining translocation products such as AML-1/ETO, the product of the AML-M2-associated t(8;21), which induces a highly modified PML and interferes with association of PML to the nuclear matrix. 82,83 Also, BCR/ABLpositive leukemic lymphoblasts express high amounts of modified PML. 82 BCR/ABL most likely targets PML-NBs by the constitutive activation of RAS.…”

“…82,83 Also, BCR/ABLpositive leukemic lymphoblasts express high amounts of modified PML. 82 BCR/ABL most likely targets PML-NBs by the constitutive activation of RAS. 82 Hence, it seems that the interference with the functionality of the PML-NBs is a common theme in leukemia.…”

Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis

“…5 Among the identified RBP-associated mRNAs, several encode important factors whose gain-or loss-offunction has been associated with altered proliferation, survival, and/or differentiation of hematopoietic cells, or with malignant transformation. [16][17][18][19][20][21][22][23][24][25][26][27] Interestingly, expression of the transcription factor and regulator of proliferation E2F3 28 is higher in CD34 ϩ bone marrow (BM) progenitors from patients with CML-BC than those with CML-CP, and is regulated by BCR/ABL through …”