Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17)

Abstract

Analysis of a variant translocation t(11;17) in a case of acute promyelocytic leukemia (APL) led to discovery of a novel zinc finger gene, PLZF, fused to the retinoic acid receptor-alpha (RAR alpha) gene. We reviewed the clinical and molecular features of five additional patients with t(11;17)-associated APL. The clinical course of three patients was characterized by early death and three experienced disseminated intravascular coagulation. Morphologically all of the patients fell in a unusual morphologic spectrum of APL, with features intermediate between M2 and M3 AML. All six patients had PLZF-RAR alpha gene fusion as detected by reverse transcription/polymerase chain reaction assay, Southern blotting, or pulsed-field gel electrophoresis. Five of the six patients failed to achieve complete remission after initial chemotherapy or differentiation therapy with all-trans retinoic acid (ATRA). A sixth patient responded to initial chemotherapy, but on relapse failed to respond to ATRA. When tested in vitro, cultured cells from three of the patients failed to differentiate in response to ATRA. APL associated with t(11;17) and fusion of the PLZF and RAR alpha genes is a discrete clinico-pathologic syndrome with a distinctly worse prognosis than t(15;17) APL.

Histone deacetylase inhibitor but not arsenic trioxide differentiates acute promyelocytic leukaemia cells with t(11;17) in combination with all‐trans retinoic acid

“…APL with t(11;17) is generally resistant or minutely sensitive to ATRA. Licht et al (1995) summarized the clinical and molecular characteristics of six patients with t(11;17). Five out of the six patients received ATRA therapy, but none had a clinical response.…”

In vivo Effects of a Histone Deacetylase Inhibitor, FK228, on Human Acute Promyelocytic Leukemia in NOD/Shi‐scid/scid Mice

“…12,13) A rare variant of APL carrying t(11;17)/PLZF-RARα responds poorly to ATRA therapy in contrast to APL with t(15;17)/PML-RARα. 14,15) The difference in sensitivity to ATRA was explained as follows. APL-specific fusion proteins, PML-RARα and PLZF-RARα, recruit the N-CoR/HDAC complex even in the presence of a physiological concentration of ATRA.…”

Characterization of apoptosis induced by protein kinase C inhibitors and its modulation by the caspase pathway in acute promyelocytic leukaemia

“…However, the most important adverse outcome of using ATRA is the rapid development of a severe form of drug resistance (Cornic & Chomienne, 1994;Mandelli, 1997). Moreover, patients with less frequent chromosomal translocations, such as t(5;17) and t(11;17), are substantially resistant to ATRA therapy (Licht et al, 1995). These findings clearly illustrate that more studies are still required to develop novel agents for complete eradication of APL.…”