Gene rearrangements in the molecular pathogenesis of acute promyelocytic leukemia

Abstract

Acute Promyelocytic Leukemia (APL) is a distinct subtype of myeloid leukemia that in the USA alone affects more than 3,000 individuals every year. APL is characterized by three distinct and unique features: i) the accumulation in the bone marrow of tumor cells with promyelocytic features; ii) the invariable association with specific translocations which always involve chromosome 17 and the Retinoic Acid Receptor alpha (RAR alpha) locus; iii) the exquisite sensitivity of APL blasts to the differentiating action of Retinoic Acid (RA). These features have led APL to become the paradigm for therapeutic approaches utilizing differentiating agents. The last 5 years have provided crucial insights into the molecular basis of APL. RAR alpha translocates in 99% of cases to a gene located on chromosome 15 that we initially named myl and subsequently has been called PML. In a few cases, RAR alpha variably translocates to chromosome 11 where it fuses to the PLZF gene or to a newly described partner, NuMA. In addition, RAR alpha is also found translocated to chromosome 5 where it fuses to the NPM gene. The cloning of variant translocations in APL and the comparative analysis of their associated products is crucial for the understanding of the molecular etiopathogenesis of the disease. The generation of animal models, i.e., transgenic mice expressing the fusion genes, will be instrumental in determining the precise contribution of these fusion genes to leukemogenesis. In fact, mice harboring a PML/RAR alpha transgene whose expression is specifically targeted to the myeloid-promyelocytic lineage develop acute myeloid leukemia with promyelocytic features. Moreover, the functional analysis of the various fusion proteins, as well as RAR alpha partners, is revealing striking common features beneath a misleading structural heterogeneity which unravels a possible unifying molecular mechanism towards APL leukemogenesis.

Tissue factors on acute promyelocytic leukemia and endothelial cells are differently regulated by retinoic acid, arsenic trioxide and chemotherapeutic agents

“…Recent work by Shibakura et al 28 showed that the downregulation effect of ATRA on TF mRNA in NB4 cells was mediated via both RAR␣ and RAR␤ nuclear receptors, and it may imply that the existence of unique fusion protein PML-RAR␣ probably involves the aberrant expression of TF in NB4 cells through its welldemonstrated dominant negative effects on wild-type RAR␣, 35 as supported by our result ( Figure 5). The practical mechanism may also involve the AP-1 sites located within the −172 to −227 region of TF gene, which have been shown to mediate the LPS-induced TF expression in THP-1 cells, 36 for Vallian et al 37 recently reported that both PML and PML-RAR␣ enhanced the AP-1-mediated transcription activity and this modulation by PML-RAR␣, but not PML, was abrogated by addition of ATRA.…”

In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications

“…APL, M3 subtype of acute myeloid leukemia (AML), accounts for more than 10% of all AMLs and is characterized by three distinctive and unique features (reviewed in Warrell et al, 1993b;Grignani et al, 1994;Pandol®, 1996;Kalantry et al, 1997;Melnick and Licht, 1999): (1) the accumulation in the bone marrow of tumor cells with promyelocytic features; (2) the invariable association with speci®c translocations which always involve chromosome 17; and (3) the exquisite sensitivity of APL blasts to the dierentiating action of retinoic acid (RA). From this point of view APL has become the paradigm for therapeutic approaches utilizing dierentiating agents.…”

“…However, although eective, treatment with RA alone in APL-1 patients induces disease remission transiently and relapse is inevitable if remission is not consolidated with chemotherapy. In addition, in the majority of cases, relapse is accompanied by RA resistance (Warrell et al, 1993b;Grignani et al, 1994;Pandol®, 1996;Kalantry et al, 1997;Melnick and Licht, 1999).…”

Chromatin dynamics and cancer

“…Certain forms of acute promyelocytic leukemia (APL) are associated to chromosome translocations involving RARα gene, and PML (Promyelocytic leukemia, t(15;17)) or PLZF (Promyelocytic leukemia zinc finger, t(11;17)), leading to the fusion proteins PML/RARα and PLZF/RARα, respectively (reviewed in ref. 34). The mechanism employed by these fusion proteins involves HDAC recruitment on target genes; this recruitment results probably in the repression of transcription of these genes, and as a consequence it inhibits cell response to retinoic acid, blocking haematopoietic terminal differentiation and leading to increased proliferation.…”