© The Author 2008. Published by Oxford University Press.
Clinical Significance of the Most Common Chromosome Translocations in Adult Acute Myeloid Leukemia
Affiliation of authors: Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Arthur G. James Cancer Hospital, Richard J. Solove Research Institute, The Ohio State University, Columbus, OH
Correspondence to: Krzysztof Mrózek, MD, PhD, Division of Hematology and Oncology, Comprehensive Cancer Center, the Arthur G. James Cancer Hospital, Richard J. Solove Research Institute, Rm 1248B, The Ohio State University, 300 West Tenth Ave, Columbus, OH 43210-1228 (e-mail: krzysztof.mrozek{at}osumc.edu).
 |
ABSTRACT |
|---|
 Top Abstract IntroductionCore-Binding Factor Acute...Acute Promyelocytic Leukemia...NotesReferences |
|---|
Acquired genetic alterations such as balanced and unbalanced chromosome aberrations and submicroscopic gene mutations and changes in gene expression strongly affect pretreatment features and prognosis of adults with acute myeloid leukemia (AML). The most frequent chromosome/molecular rearrangements, that is, t(8;21)(q22;q22)/RUNX1-RUNX1T1 and inv(16)(p13q22)/t(16;16)(p13;q22)/CBFB-MYH11 characteristic of core-binding factor (CBF) AML and t(15;17)(q22;q12
21)/PML-RARA characteristic of acute promyelocytic leukemia (APL), confer favorable clinical outcome when patients receive optimal treatment, that is, regimens that include high-dose cytarabine for CBF AML and all-trans-retinoic acid and/or arsenic trioxide for APL. Recently, mutations in such genes as KIT in CBF AML and FLT3 in APL have been correlated with clinical features and/or outcome of patients with these AML subtypes, and microarray gene expression profiling has been successfully used for diagnostic purposes and to provide biologic insights. These data underscore the value of genetic testing for common translocations for diagnosis, prognostication, and, increasingly, selecting therapy in acute leukemia.
|
INTRODUCTION |
|---|
|
TopAbstractIntroductionCore-Binding Factor Acute...Acute Promyelocytic Leukemia...NotesReferences |
|---|
Acute myeloid leukemia (AML) is very heterogeneous at the cytogenetic and molecular genetic levels. Over the last 30 years, several specific recurrent chromosome aberrations have been described in AML, both unbalanced, such as deletions, isochromosomes, dicentric chromosomes, duplications, and unbalanced translocations, and balanced such as reciprocal translocations, insertions, and inversions (1). Balanced chromosome rearrangements are detected in approximately 25%–30% of adults with de novo AML (2–4) (Table 1) and have attracted a great deal of attention not only because their molecular dissection has led to identification of genes involved in leukemogenesis but also because specific translocations and inversions are associated with clinical features and treatment outcome of patients harboring them. In this article, we discuss clinical implications of the three most common balanced rearrangements in AML, namely t(8;21)(q22q;22), inv(16)(p13q22)/t(16;16)(p13;q22), and t(15;17)(q22;q12
21).
|
|
Core-Binding Factor Acute Myeloid Leukemia With t(8;21)(q22q;22) and inv(16)(p13q22)/t(16;16)(p13;q22) |
|---|
|
TopAbstractIntroductionCore-Binding Factor Acute...Acute Promyelocytic Leukemia...NotesReferences |
|---|
Translocation (8;21) was the first reciprocal translocation in AML that was identified using banding techniques in 1973 (5). It is among the most frequent recurrent chromosome aberrations in adult de novo AML, being detected in 6% of patients (2). Both the standard t(8;21) and its relatively rare variants, that is, complex translocations involving three or four different chromosomes that consistently affect bands 8q22 and 21q22 or the insertions ins(8;21)(q22;q22q22) or ins(21;8)(q22;q22q22) (6), disrupt the RUNX1 gene that encodes subunit
of core-binding factor (CBF), and lead to the creation of a chimeric gene RUNX1-RUNX1T1(AML1-ETO) (7,8). The presence of t(8;21)/RUNX1-RUNX1T1 is associated with AML with maturation in the neutrophil lineage (FAB M2). It has been suggested that characteristic pink-colored cytoplasm of neutrophils and an increased number of eosinophil precursors without abnormalities typical for AML with inv(16)/t(16;16) morphologically distinguish patients with t(8;21) from other patients with AML M2 who do not harbor t(8;21)/RUNX1-RUNX1T1 (9,10). The second rearrangement associated with CBF AML, inv(16), is a much subtler rearrangement that might be overlooked in chromosome preparations of suboptimal quality. This in part explains why it was discovered 9 years after t(8;21), in 1982 (11,12). Large studies have shown that inv(16), and its less common variant t(16;16), are found in 7% of adults with de novo AML (2). Both inv(16) and t(16;16) involve the CBFB gene, encoding subunit β of CBF, that is fused with the MYH11 gene (13,14). Patients with inv(16)/t(16;16) have a unique marrow morphology with the presence of abnormal eosinophils (FAB M4Eo) (15).
The prognosis of patients with inv(16)/t(16;16) and those with t(8;21) is relatively favorable. In 1994, Bloomfield et al. (16,17) were the first to show that higher doses of postinduction cytarabine (HiDAC) were capable of improving outcome for patients with CBF AML. It was later shown that treatment outcome is improved by postremission therapy with three or four cycles of HiDAC as opposed to one cycle (18,19). Because of these similarities in response to treatment and of involvement of subunits of CBF at the molecular level, many clinical trials and reports have combined patients with inv(16)/t(16;16) with those with t(8;21) into one, favorable risk prognostic category of AML.
Nevertheless, despite similarities, patients with t(8;21) differ from those with inv(16)/t(16;16) with respect to many pretreatment features. They are more frequently African American and less frequently white (20,21) and have lower white blood cell (WBC) counts (20–22) and percentages of blood and bone marrow (BM) blasts (20), less often extramedullary involvement (20,22), specifically lymphadenopathy (20,22), splenomegaly (20), gingival hypertrophy (20), and skin/mucosa involvement (22), and a different pattern of secondary cytogenetic abnormalities. Whereas about 70% of patients with t(8;21) have at least one additional chromosome aberration, only one-third of patients with inv(16)/t(16;16) do (20–22). Moreover, the most frequent secondary aberrations among t(8;21)-positive patients are loss of a sex chromosome, -Y in men and -X in women, and deletion of 9q, whereas in inv(16)/t(16;16)-positive patients, the most common are +22, +8, deletion of 7q, and +21 (20–22).
Complete remission (CR) rates are relatively high and very similar in both cytogenetic groups — 85% to 89% (20–22), with the probability of CR achievement adversely affected by lower platelet counts (20). On the other hand, lower CR probability is associated with hepatomegaly only in inv(16)/t(16;16) patients, and with higher BM blasts and, unexpectedly, nonwhite race only in the t(8;21) group. Nonwhite t(8;21) patients had 5.7 times the odds of failing induction compared with white patients. The reasons for such a difference are currently unknown (20).
In univariable analyses, neither relapse risk nor overall survival (OS) differed significantly between t(8;21) and inv(16)/t(16;16) groups (20–22). However, after adjusting for age, log(WBC), and log(platelets), the OS of t(8;21) patients was significantly shorter than OS of those with inv(16)/t(16;16) (20). The difference may be in part explained by a dissimilar response to salvage treatment because t(8;21) patients had a significantly shorter survival after relapse than inv(16)/t(16;16) patients in three large, independent studies (20–22). Moreover, among inv(16)/t(16;16) patients, those with secondary +22 had a significantly lower cumulative incidence of relapse (CIR) than those with isolated inv(16)/t(16;16) in the Cancer and Leukemia Group B (CALGB) study (20) and longer relapse-free survival (RFS) than patients without +22 in the German AML Intergroup study (22). In the latter study (22), -Y conferred a shorter OS in t(8;21) patients, but this was not confirmed by other research groups (20,21). Marcucci et al. (20) observed a possible interaction between secondary chromosome aberrations and race in t(8;21) patients. Nonwhite patients with secondary aberrations other than del(9q) had shorter OS than those who harbored an isolated t(8;21) or a secondary del(9q). In contrast, secondary aberrations did not influence OS of white t(8;21) patients.
Recent studies have revealed that 20%–45% of CBF AML patients harbor mutations in the KIT gene. Among patients with t(8;21), the presence of KIT mutations, and especially mutations in exon 17 that encodes the activation loop in the kinase domain of KIT, have been associated with inferior OS (23–25), event-free survival (EFS) (24,25), incidence of relapse (23), RFS (25), and CIR (26). The prognostic impact of KIT mutations in inv(16)/t(16;16) patients has been less clear. KIT mutations in exon 8 unfavorably affected the relapse rate, but not OS, in one study (27) but had no prognostic significance in two smaller series (23,25). The most recent, relatively large, study (26) performed on inv(16)/t(16;16) patients similarly treated with HiDAC demonstrated that the presence of all KIT mutations bestowed a higher CIR. Notably, the difference in CIR was primarily caused by the KIT exon 17 mutations. Patients with exon 17 mutations had more than six times higher CIR than those without KIT mutations. Multivariable analyses revealed that KIT mutations, both those in exon 17 and exon 8, impacted negatively on OS after adjusting for sex (26). These findings should be corroborated.
The presence of KIT mutations in CBF AML patients is important because they constitute potential therapeutic targets for tyrosine kinase (TK) inhibitors. Notably, particular TK inhibitors are active against specific KIT mutations, for example, imatinib is active against exon 17 mutations involving N822 in the activation loop, or variants of exon 8 mutations, but not against exon 17 mutations involving D816. The latter mutations can be successfully targeted with other TK inhibitors, such as dasatinib and PKC412. Thus, it is essential to determine the exact type of KIT mutation in each patient (26). Future clinical trials will likely investigate the efficacy of TK inhibitors as part of therapy administered to patients with CBF AML.
While the aforementioned secondary chromosome aberrations and KIT mutations seem to be useful prognostic markers, they are not present in a substantial proportion of CBF AML patients, for whom other predictors of outcome are thus needed. It appears that further prognostic stratification might be possible using gene expression profiling (GEP) (28). Earlier GEP studies were successful in identifying diagnostic gene expression signatures that allowed reliable separation of CBF AML patients with t(8;21) and those with inv(16)/t(16;16) from other cytogenetic/molecular genetic subgroups of AML (eg, patients with 11q23 aberrations, t(15;17), -7/del(7q), or a normal karyotype) (29–31). In a study of Haferlach et al. (32) that analyzed GEP in 13 clinically relevant leukemia subtypes, which in addition to several cytogenetic groups of AML also included B-cell and T-cell ALL, chronic myeloid leukemia, and chronic lymphocytic leukemia, both t(8;21) and inv(16)/t(16;16) patients were among those correctly identified with the highest degree of accuracy, with a 100% specificity and 100% sensitivity. Several specific genes were found as over- and underexpressed within gene expression signatures of patients with t(8;21) and inv(16)/t(16;16), including consistent overexpression of, respectively, the RUNX1T1 and MYH11 genes (30,31,33). Ongoing analyses of these deregulated gene expression patterns will likely result in better understanding of genetic pathways involved in leukemogenesis of CBF AML.
Additionally, a recent study applied GEP in patients with t(8;21) and in a subset of inv(16)/t(16;16)–positive patients, that is, those who had inv(16) or t(16;16) as a sole chromosome aberration and did not harbor KIT mutations, to test whether this technique can improve outcome prediction in CBF AML patients without established prognostic factors (28). For both groups, gene expression–based outcome predictors for EFS were constructed, and they resulted in identification of patient groups with strikingly different clinical outcome. While these results require corroboration, it appears that GEP may become a valuable tool for both diagnosis and prognostication of CBF AML.
|
Acute Promyelocytic Leukemia With t(15;17)(q22;q1221) and Variants
|
|---|
|
TopAbstractIntroductionCore-Binding Factor Acute...Acute Promyelocytic Leukemia...NotesReferences |
|---|
Acute promyelocytic leukemia (APL), described as a separate entity in 1957 (34), and for many years associated with an extremely poor outcome, comprises 7% of adult AML cases (2). In 1977, Rowley et al. (35) demonstrated that t(15;17) was specific for APL, and 13 years later it was shown that t(15;17) creates the PML-RARA gene fusion (36). The PML-RARA protein binds to corepressor/histone deacetylase (HDAC) complexes with higher affinity than the wild-type RARA, leading to aberrant chromatin acetylation and alterations of chromatin conformation inhibiting the normal transcription of genes regulated by RARA. This blocks cell differentiation and leads to the accumulation of abnormal promyelocytes (37). Notably, therapeutic doses of all-trans-retinoic acid (ATRA) change conformation of the PML-RARA protein and release corepressor/HDAC complexes resulting in transcriptional activation of downstream target genes. Additionally, both ATRA and arsenic trioxide, a compound also used to treat APL, induce proteolysis of PML-RARA protein resulting in granulocytic differentiation of the leukemic blasts (37).
While more than 90% of APL patients carry t(15;17) or its complex variants, approximately 4% of patients harbor an insertion of chromosomal material from 17q with the RARA gene into 15q22, the PML gene locus (38). Most of these insertions are cryptic, associated with a normal karyotype, and detectable only using reverse transcription–polymerase chain reaction (RT–PCR) and/or fluorescence in situ hybridization (FISH). In about one-third of APL patients with t(15;17), this translocation is accompanied by at least one secondary aberration, most commonly +8 or a partial trisomy of 8q (39–41). The presence of secondary chromosome abnormalities did not impact on prognosis of APL patients treated with chemotherapy and ATRA (40–42). A small proportion of APL patients do not have t(15;17)/PML-RARA but harbor other chromosomal aberrations and gene fusions such as t(11;17)(q23;q1221)/PLZF-RARA, t(11;17)(q13;q1221)/NUMA1-RARA, t(5;17)(q35;q1221)/NPM1-RARA, and dup(17)(q21.3q23)/STAT5b-RARA (43). With the exception of t(11;17)(q23;q1221)/PLZF-RARA, all these rearrangements and t(15;17) are very strongly correlated with characteristic marrow morphology in which abnormal promyelocytes predominate (FAB M3) (15).
Up to 50% of APL patients harbor mutations of the FLT3 gene in addition to t(15;17)/PML-RARA (44–47). The more frequent FLT3 mutation type, detected in 34%–38% of patients, is internal tandem duplication within the FLT3 juxtamembrane domain (exons 14 and 15) (FLT3-ITD). A missense mutation within the activation loop of the tyrosine kinase domain (exon 20) of FLT3 (FLT3-TKD) is detected in 6%–13% of patients (44–47). Occasionally, both FLT3-ITD and FLT3-TKD can be found in the same patient (44–47). Both types of FLT3 mutations promote constitutive phosphorylation of the FLT3 protein thereby impairing normal hematopoiesis and contributing to leukemogenesis, albeit functional properties of FLT3-TKD differ from those of FLT3-ITD, and are more similar to the signal transduction properties of ligand-activated wild-type FLT3 (48).
Clinically, the presence of FLT3-ITD has been associated with higher WBC, the microgranular morphologic variant of APL (FAB-M3v), and the bcr3 breakpoint in the PML gene resulting in creation of the short (S) isoform of the PML-RARA transcript (44–47). FLT3-ITD, higher WBC, bcr3 PML breakpoint, as well as CD2 and CD15 expression have been recently associated with a higher risk of developing thrombotic complications by APL patients treated with ATRA and idarubicin (49). In one study, APL patients with FLT3-ITD were also less likely to have any secondary chromosome aberration in addition to t(15;17) (45). The authors suggested that secondary chromosome aberrations present in APL patients without FLT3-ITD may provide the leukemic cells with a proliferative advantage similar to that resulting from the acquisition of FLT3-ITD (45).
Although Gale et al. (45) observed a higher incidence of induction death among patients with FLT3-ITD, neither they nor another study (44) reported a significant difference in CR rates between APL patients with and without FLT3-ITD. Moreover, unlike in cytogenetically normal patients with AML, for whom FLT3-ITD constitutes an established adverse prognostic factor for both remission duration and survival (50), in APL, none of four large studies was able to demonstrate significant differences in risk of relapse (44,45), CIR (47), disease-free survival (DFS) (44), EFS (46), or OS (45–47) between patients with and without FLT3-ITD. However, Callens et al. (47) reported that among the relatively infrequent patients who relapse those with FLT3-ITD have a significantly shorter survival compared with survival of patients without FLT3-ITD. In addition, Gale et al. (45) observed borderline significantly worse OS, but not relapse risk, in APL patients with FLT3-TKD compared with those with wild-type FLT3, and there was a trend toward worse EFS for FLT3-TKD–positive patients in a study of Kuchenbauer et al. (49), although no significant difference in CIR or OS was observed by Callens et al. (47). Because FLT3-TKD is much less common than FLT3-ITD in APL, its potential unfavorable impact on treatment outcome should be studied further in large series of patients.
Interestingly, GEP studies, which, as mentioned earlier, can reliably differentiate APL from other subtypes of AML (29–32), revealed, using an unsupervised analysis, the existence of two major clusters within APL patients based on gene expression signatures (51). The first cluster consisted almost exclusively of patients with FAB-M3v morphology, high WBC at presentation, the short PML-RARA isoform (bcr3), and FLT3-ITD, whereas APL cases with classical morphology, long PML-RARA isoform (bcr1) transcript, leucopenia, and wild-type FLT3 were mainly grouped in the second cluster (51). Additional supervised analysis established that it was the FLT3 gene status that was the parameter best associated with the two clusters of APL patients. Marasca et al. (51) identified 92 genes that were upregulated in patients with FLT3-ITD that included genes involved in cytoskeleton organization, cell adhesion, cancer invasiveness and metastasis, embryogenesis and cell growth, and inflammation and coagulation processes. Consistent with an association between FLT3-ITD and microgranular morphology, genes encoding proteins known to be present in granulocytic granules were found among 55 genes downregulated in FLT3-ITD–positive patients.
Fast and accurate diagnosis of APL is of paramount importance because the disease is often accompanied by disseminated intravascular coagulation, which can be aggravated or even triggered by induction chemotherapeutic regimens that do not include ATRA. Likewise, it is important to determine which of the APL-associated translocations are present because patients with t(11;17)(q23;q1221)/PLZF-RARA are resistant to standard ATRA-based treatment. Although t(11;17)-positive APL has been reported to have distinguishing morphologic and immunophenotypic characteristics (52), the diagnosis should always be supported by results of cytogenetic, FISH, and/or RT–PCR analyses. RT–PCR determination of the particular PML-RARA isoform in each case is important for disease monitoring because the probability of relapse is increased in patients who after 3–4 cycles of ATRA and chemotherapy are still positive for the presence of the PML-RARA transcript, whereas persistent negative RT–PCR results correlate with long-standing remissions in most, but not all, patients (53).
The historically very poor prognosis of APL patients with t(15;17)/PML-RARA, with a median survival of 2 weeks in the 1960s, has become favorable with the use of therapies containing anthracyclines, ATRA, and/or arsenic trioxide, with a cure rate exceeding 80% in recent studies (54). Recently, gemtuzumab ozogamicin, which is a monoclonal antibody directed against CD33, an antigen present on leukemic blasts of almost all patients with APL, has been shown to be effective in producing molecular remissions in both newly diagnosed and relapsed patients (55). In one study, a combination of gemtuzumab, ATRA and arsenic trioxide was successfully used to induce prolonged second CRs in APL patients who had experienced first hematologic recurrence (56). Further studies are necessary to establish long-term consequences of this and other treatment regimens containing gemtuzumab.
|
NOTES |
|---|
Supported in part by National Cancer Institute, Bethesda, MD, grants CA101140 and CA16058, and the Coleman Leukemia Research Foundation.
|
REFERENCES |
|---|
|
TopAbstractIntroductionCore-Binding Factor Acute...Acute Promyelocytic Leukemia...NotesReferences |
|---|
1. Mrózek K, Heinonen K, Bloomfield CD. Clinical importance of cytogenetics in acute myeloid leukaemia. Best Pract Res Clin Haematol (2001) 14:19–47.[Medline]
2. Byrd JC, Mrózek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood (2002) 100:4325–4336.
3. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood (2000) 96:4075–4083.
4. Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood (2001) 98:1312–1320.
5. Rowley JD. Identificaton of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann Genet. (1973) 16:109–112.[Web of Science][Medline]
6. Mrózek K, Prior TW, Edwards C, et al. Comparison of cytogenetic and molecular genetic detection of t(8;21) and inv(16) in a prospective series of adults with de novo acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol (2001) 19:2482–2492.
7. Erickson P, Gao J, Chang K-S, et al. Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood (1992) 80:1825–1831.
8. Miyoshi H, Kozu T, Shimizu K, et al. The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript. EMBO J (1993) 12:2715–2721.[Web of Science][Medline]
9. Bitter MA, Le Beau MM, Rowley JD, Larson RA, Golomb HM, Vardiman JW. Associations between morphology, karyotype, and clinical features in myeloid leukemias. Hum Pathol (1987) 18:211–225.[Web of Science][Medline]
10. Nakamura H, Kuriyama K, Sadamori N, et al. Morphological subtyping of acute myeloid leukemia with maturation (AML-M2): homogeneous pink-colored cytoplasm of mature neutrophils is most characteristic of AML-M2 with t(8;21). Leukemia (1997) 11:651–655.[CrossRef][Web of Science][Medline]
11. Bloomfield CD, Arthur DC. Evaluation of leukemic cell chromosomes as a guide to therapy. Blood Cells (1982) 8:501–518.[Web of Science][Medline]
12. Arthur DC, Bloomfield CD. Partial deletion of the long arm of chromosome 16 and bone marrow eosinophilia in acute nonlymphocytic leukemia: a new association. Blood (1983) 61:994–998.
13. Liu P, Tarlé SA, Hajra A, et al. Fusion between transcription factor CBFβ/PEBP2β and a myosin heavy chain in acute myeloid leukemia. Science (1993) 261:1041–1044.
14. Shurtleff SA, Meyers S, Hiebert SW, et al. Heterogeneity in CBFß/MYH11 fusion messages encoded by the inv(16)(p13q22) and the t(16;16)(p13;q22) in acute myelogenous leukemia. Blood (1995) 85:3695–3703.
15. Jaffe ES, Harris NL, Stein H, Vardiman JW. editors World Health Organization classification of tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues (2001) Lyon, France: IARC Press.
16. Bloomfield CD, Lawrence D, Arthur DC, Berg DT, Schiffer CA, Mayer RJ. Curative impact of intensification with high-dose cytarabine (HiDAC) in acute myeloid leukemia (AML) varies by cytogenetic group. Blood (1994) 84:111a.
17. Bloomfield CD, Lawrence D, Byrd JC, et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res. (1998) 58:4173–4179.
18. Byrd JC, Dodge RK, Carroll A, et al. Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered. J Clin Oncol (1999) 17:3767–3775.
19. Byrd JC, Ruppert AS, Mrózek K, et al. Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): results from CALGB 8461. J Clin Oncol (2004) 22:1087–1094.
20. Marcucci G, Mrózek K, Ruppert AS, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol (2005) 23:5705–5717.
21. Appelbaum FR, Kopecky KJ, Tallman MS, et al. The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations. Br J Haematol (2006) 135:165–173.[CrossRef][Web of Science][Medline]
22. Schlenk RF, Benner A, Krauter J, et al. Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol (2004) 22:3741–3750.
23. Cairoli R, Beghini A, Grillo G, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias. An Italian retrospective study. Blood (2006) 107:3463–3468.
24. Schnittger S, Kohl TM, Haferlach T, et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood (2006) 107:1791–1799.
25. Boissel N, Leroy H, Brethon B, et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia (2006) 20:965–970.[CrossRef][Web of Science][Medline]
26. Paschka P, Marcucci G, Ruppert AS, et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B study. J Clin Oncol (2006) 24:3904–3911.
27. Care RS, Valk PJM, Goodeve AC, et al. Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. Br J Hematol (2003) 121:775–777.[CrossRef][Web of Science][Medline]
28. Paschka P, Radmacher MD, Marcucci G, et al. Gene expression profiling improves outcome prediction in adult core binding factor (CBF) acute myeloid leukemia (AML): a Cancer and Leukemia Group B (CALGB) study. J Clin Oncol (2007) 25((suppl)):359s.
29. Schoch C, Kohlmann A, Schnittger S, et al. Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles. Proc Natl Acad Sci USA (2002) 99:10008–10013.
30. Bullinger L, Döhner K, Bair E, et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med (2004) 350:1605–1616.
31. Valk PJM, Verhaak RGW, Beijen MA, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med (2004) 350:1617–1628.
32. Haferlach T, Kohlmann A, Schnittger S, et al. Global approach to the diagnosis of leukemia using gene expression profiling. Blood (2005) 106:1189–1198.
33. Ichikawa H, Tanabe K, Mizushima H, et al. Common gene expression signatures in t(8;21)- and inv(16)-acute myeloid leukaemia. Br J Hematol (2006) 135:336–347.[CrossRef][Web of Science][Medline]
34. Hillestad LK. Acute promyelocytic leukemia. Acta Med Scand (1957) 159:189–194.[Web of Science][Medline]
35. Rowley JD, Golomb HM, Dougherty C. 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia. Lancet (1977) 1:549–50.[Web of Science][Medline]
36. de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor gene to a novel transcribed locus. Nature (1990) 347:558–561.[CrossRef][Web of Science][Medline]
37. Jing Y. The PML-RAR fusion protein and targeted therapy for acute promyelocytic leukemia. Leuk Lymphoma (2004) 45:639–648.[CrossRef][Web of Science][Medline]
38. Grimwade D, Biondi A, Mozziconacci M-J, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Blood (2000) 96:1297–1308.
39. Slack JL, Arthur DC, Lawrence D, et al. Secondary cytogenetic changes in acute promyelocytic leukemia
prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene: a Cancer and Leukemia Group B study. J Clin Oncol (1997) 15:1786–1795.
40. De Botton S, Chevret S, Sanz M, et al. Additional chromosomal abnormalities in patients with acute promyelocytic leukaemia (APL) do not confer poor prognosis: results of APL 93 trial. Br J Hematol (2000) 111:801–806.[CrossRef][Web of Science][Medline]
41. Hernández JM, Martín G, Gutiérrez NC, et al. Additional cytogenetic changes do not influence the outcome of patients with newly diagnosed acute promyelocytic leukemia treated with an ATRA plus anthracyclin based protocol. A report of the Spanish group PETHEMA. Haematologica (2001) 86:807–813.
42. Sanz MA, Tallman MS, Lo-Coco F. Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood (2005) 105:3019–3025.
43. Zelent A, Guidez F, Melnick A, Waxman S, Licht JD. Translocations of the RAR gene in acute promyelocytic leukemia. Oncogene (2001) 20:7186–7203.[CrossRef][Web of Science][Medline]
44. Noguera NI, Breccia M, Divona M, et al. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia (2002) 16:2185–2189.[CrossRef][Web of Science][Medline]
45. Gale RE, Hills R, Pizzey AR, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood (2005) 106:3768–3776.
46. Kuchenbauer F, Schoch C, Kern W, Hiddemann W, Haferlach T, Schnittger S. Impact of FLT3 mutations and promyelocytic leukaemia-breakpoint on clinical characteristics and prognosis in acute promyelocytic leukaemia. Br J Hematol (2005) 130:196–202.[CrossRef][Web of Science][Medline]
47. Callens C, Chevret S, Cayuela J-M, et al. Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia (2005) 19:1153–1160.[CrossRef][Web of Science][Medline]
48. Choudhary C, Schwäble J, Brandts C, et al. AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations. Blood (2005) 106:265–273.
49. Breccia M, Avvisati G, Latagliata R, et al. Occurrence of thrombotic events in acute promyelocytic leukemia correlates with consistent immunophenotypic and molecular features. Leukemia (2007) 21:79–83.[CrossRef][Web of Science][Medline]
50. Mrózek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood (2007) 109:431–448.
51. Marasca R, Maffei R, Zucchini P, et al. Gene expression profiling of acute promyelocytic leukaemia identifies two subtypes mainly associated with flt3 mutational status. Leukemia (2006) 20:103–114.[CrossRef][Web of Science][Medline]
52. Sainty D, Liso V, Cantù-Rajnoldi A, et al. A new morphologic classification system for acute promyelocytic leukemia distinguishes cases with underlying PLZF/RARA gene rearrangements. Blood (2000) 96:1287–1296.
53. Lo-Coco F, Ammatuna E. The biology of acute promyelocytic leukemia and its impact on diagnosis and treatment. Hematology Am Soc Hematol Educ Program (2006) 156–161.
54. Frankfurt O, Tallman MS. Strategies for the treatment of acute promyelocytic leukemia. J Natl Compr Canc Netw (2006) 4:37–50.[Medline]
55. Lo Coco F, Ammatuna E, Noguera N. Treatment of acute promyelocytic leukemia with gemtuzumab ozogamicin. Clin Adv Hematol Oncol (2006) 4:57–62. 76–77.[Medline]
56. Aribi A, Kantarjian HM, Estey EH, et al. Combination therapy with arsenic trioxide, all-trans retinoic acid, and gemtuzumab ozogamicin in recurrent acute promyelocytic leukemia. Cancer (2007) 109:1355–1359.[Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. S. Rabkin and S. Janz Overview of Mechanisms and Consequences of Chromosomal Translocation J Natl Cancer Inst Monographs, July 1, 2008; 2008(39): 1 - 1. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||