Acute myeloid leukemia in four patients with t(8;21) treated with all-trans retinoic acid as a single agent

Abstract

Acute myeloid leukemia (AML) is characterized by a block of terminal differentiation of hematopoietic precursors and the repression of normal hematopoiesis by expanding immature blasts. AMLs are frequently associated with specific chromosomal translocations, resulting in the generation of chimeric genes. These genes encode chimeric transcription factors, which possess chromatin-modeling activity and deregulate the transcription of specific target genes [1].The use of all-trans retinoic acid (ATRA) has significantly improved the treatment results in acute promyelocytic leukemia (APL). The great majority of patients treated with ATRA as a single agent will experience a relapse within a few months. Nevertheless, when used in combination with conventional chemotherapy, the efficacy of ATRA increases dramatically, improving the long-term survival of APL patients to 75% [2]. In non-APL AML, the effects of ATRA are less clear. The majority of non-APL AML blast cells are sensitive to ATRA in vitro, but a considerable proportion of the cells are resistant [3]. This stresses the need for more knowledge about the molecular mechanisms of ARTA and the demand for tools to predict ARTA sensitivity. A distinct subset of AML, making up *10% of all AML cases, is characterized by a t(8;21)(q22;q22) translocation and, morphologically, by the presence of myeloblasts, showing maturation in the neutrophil lineage. The t(8;21) juxtaposes the RUNX1 gene on chromosome 21 with the CBFT1 gene on chromosome 8, generating the AML1-ETO fusion transcription factor. We now present four patients with AML treated with ATRA alone, who were initially misdiagnosed as APL according to the FrenchAmerican-British (FAB) classification.Case 1: In July 2007, a 25-year-old man with a fever and cough was admitted to other hospital. Peripheral blood counts showed hemoglobin (Hb) 65 g/L, white blood cells (WBC) 23.3610 9 /L, blood platelet cells (plts) 69610 9 /L. Bone marrow examination revealed a hypercellularity with 16% myeloblasts and 52% abnormal promyelocytes in the existence of Auer rods, large granules packed in cytoplasm and nuclei irregular in size and shape. Diagnosis was made as APL based on FAB classification. The patient received arsenic trioxide (10 mg/day) for 30 days, WBC was 15.8610 9 /L with normal platelet count, and the level of promyelocytes in bone marrow was reduced to 18.4%. Then, he was admitted to our hospital and continued to receive arsenic trioxide. At this point, the diagnosis was changed from APL to t(8;21) AML according to karyotype analysis, flow cytometric immunophenotyping of bone marrow cells and reverse transcription polymerase chain reaction (RT-PCR) ( Table I). Interphase fluorescence in situ hybridization (FISH) showed 96.7% of AML1-ETO fusion gene in bone marrow cells but failed to demonstrate the presence of PML-RARa fusion gene. Myeloblasts in peripheral blood disappeared, and promyelocytes decreased from 18.4% to 9.16% by the 50th day after arsenic trioxide treatment was initiated. However, FISH analysis for AML1-E...

The ATRA-21 gene-expression model predicts retinoid sensitivity in CEBPA double mutant, t(8;21) and inv(16) AML patients

“…Clear experimental validation of these results is required and the approach that we are currently pursuing involves exposure of primary blasts obtained from AML patients to ATRA in vitro. Nevertheless, it must be emphasized that the validity of the predictions on ATRA sensitivity based on our model is fully supported by the results obtained in the two above-mentioned clinical studies 8,9 . Finally, it should be mentioned that it is entirely possible that our analysis may overlook specific subgroups of patients or individual cases that may be sensitive to ATRA.…”

“…As for the AML classification based on the presence/absence of the most prevalent genetic rearrangements, the cases showing an inversion of chromosome 16 [ inv(16) ] or a t(8;21) chromosomal translocation are characterized by ATRA-21 predictions well above the average of the remainder AML population. With respect to this, it is interesting to notice that a case report study demonstrates that ATRA induces one partial and three complete remissions in four t(8;21) AML patients initially misdiagnosed as APL cases 9 . As for the AML subtypes defined by recurrent gene mutations, the only cluster predicted to be responsive to ATRA belongs to the larger group of patients characterized by biallelic mutations of the CEBPA gene.…”

Co-expression of t(15;17) and t(8;21) in a Case of Acute Promyelocytic Leukemia: Review of the Literature

“…Interestingly, one patient who had a temporary response (without CR) with ATRA achieved CR after a combined treatment including daunorubicin and cytarabine. The presence of both AML1-ETO and PML-RARα fusion genes were detected by RT-PCR in this patient [23]. The authors suggested that AML1-ETO and PML-RARα recruit a multiprotein complex containing histone deacetylases (HDACs) on crucial myeloid differentiation via several co-repressors, which leads to a cell differentiation block [24].…”

An ATRActive future for differentiation therapy in AML

“…Griggs et al described one patient with normal cytogenetic-AML who was refractory to standard induction chemotherapy, but who entered a remission upon treatment with ATRA 45 mg/m2/day for 34 days 23 . Qian et al reported the effects of single-agent ATRA in four t(8;21) AML patients who were originally misdiagnosed as APL 24 . In one case, a patient was treated with arsenic trioxide for 50 days with no response; he was thereafter transitioned to 40 mg/d ATRA, and cleared his marrow of blasts within one week, but relapsed three weeks later.…”