急性髓系白血病伴新的t(8;21)变异易位——t(7;21)(p21;q22)易位

目的:探讨1例急性髓系白血病(acute myeloid leukemia,AML)伴新的t(8; 21)变异易位即t(7; 21)(p21;q22)易位患者的临床与分子生物学特点.方法:将AML患者的骨髓细胞经短期培养后按常规方法制备染色体,R显带进行核型分析;利用AML1/ETO双色双融合探针进行荧光原位杂交检测;实时荧光定量PCR法检测AML1/ETO融合基因的转录本拷贝数.结果:患者的常规细胞遗传学分析结果显示为t(7; 21)(p21;q22)易位.86％的骨髓细胞为AML1/ETO融合基因阳性,融合基因转录本为51 440个拷贝/10 000个内参Ab1基因拷贝.结论:t(7;21)(p21; q22)是一种新的t(8; 21)(q22; q22)变异易位,与其他类型的t(8; 21)变异易位相似,预示有良好预后.     

Molecular and clinical advances in core binding factor primary acute myeloid leukemia: a paradigm for translational research in malignant hematology

Clonal chromosomal abnormalities are the most important prognostic indicators in acute myeloid leukemia (AML). Recent advances in molecular biology have allowed structural and functional characterization of many of these genomic rearrangements and have provided evidence for their primary role in leukemogenesis. Two of the most prevalent cytogenetic subtypes of adult primary or de novo AML, t(8;21)(q22;q22) and inv(16)(p13q22), are characterized by disruption of the AML1(CBF alpha 2) gene at 21q22 and the CBF beta gene at 16q22, respectively. Both genes encode a subunit of core binding factor (CBF), a regulator of normal hematopoiesis. At the molecular level, t(8;21)(q22;q22) and inv(16)(p13q22) result in the creation of novel fusion genes, AML1/ETO and CBF beta/MYH11, whose structures and functions are being successfully characterized by in vitro studies and transgenic animal models. Detection of t(8;21)(q22;q22) or inv(16)(p13q22) in adult patients with primary AML is a favorable independent prognostic indicator for achievement of cure after intensive chemotherapy or bone marrow transplantation and may serve as a paradigm for risk-adapted treatment in AML. The purpose of this review is to summarize the recent advances in the molecular biology and clinical management of t(8;21)(q22;q22) and inv(16)(p13q22) primary AML, collectively referred to here as CBF AML.     

Cytogenetic Characteristics of de novo Acute Myeloid Leukemia in Southern Vietnam

Background: The cytogenetic characteristics are important factors for risk stratification at diagnosis of acute myeloid leukemia (AML); however, cytogenetic profile of Vietnamese patients with AML remains undetermined. In this study, we present the chromosomal data of de novo AML patients in Southern Vietnam. Methods: We performed cytogenetic testing for 336 AML patients using G banding. If the patients had suspected abnormalities, fluorescence in situ hybridization with probes of inv(3)(q21q26)/t(3;3)(q21;q26), 5q31, 7q31, t(8;21)(q21.3;q22), 11q23, t(15;17)(q24;q21), inv(16)(p13q22)/t(16;16)(p13;q22)were analyzed. Patients without above aberrations or with normal karyotype were tested by fluorescence in situ hybridization using probe 11q23. Results: We found that the median age was 39 years. According to French – American – British classification, AML-M2 is the most frequent type with 35.1%. Chromosomal abnormalities were detected in 208 cases, accounting for 61.9%. Among structural abnormalities, t(15;17) was the most common (19.6%), followed by t(8;21) and inv (16)/t(16;16) in 10.1% and 6.2%, respectively. In perspective of chromosomal numerical abnornmalities, loss of sex chromosomes are the most common (7.7%), followed by +8 in 6.8%, -7/del(7q) in 4.4%, +21 in 3.9% and -5/del (5q) in 2.1%. The prevalence of addditional cytogenetic aberrations accompanying with t(8;21) and inv(16)/t(16;16) were 82.4% and 52.4%, repectively. None of +8 cases was associated with t(8;21). Regarding cytogenetic risk assessment according to European Leukemia Net 2017, there were 121 (36%) patients in favorable-risk, 180 (53.6%) in intermediate-risk and 35 (10.4%) in adverse-risk group. Conclusion: In conclusion, this is the first comprehensive cytogenetic profile of Vietnamese patients diagnosed with de novo AML, which helps clinical doctors in prognostic classification for AML patients in Southern Vietnam.     

Specific chromosomal aberrations in de novo acute myeloid leukemia: a comparative analysis of results with a report of three novel chromosomal rearrangements t(7;14)(q35;q13), t(8;18)(p11.2;q12), t(13;15) in Indian population

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with regard to morphology, immunophenotype, and genetic rearrangements. Multiple recurrent chromosomal aberrations have been identified by conventional cytogenetic analysis, which is now widely recognized as one of the most important diagnostic and prognostic determinants in AML. Method: Conventional cytogenetic analysis was done on 200 de novo AML subjects. Results: Of these, 176 (88%) were successfully karyotyped and 24 (12%) showed culture failure. Among the176 subjects, 101 (57.4%) were abnormal and 75 (42.6%) showed an apparently normal karyotype. The various aberrations observed were t(8;21)(q22;q22) (5.2%); t(15;17) (q22;q11-21) (9%); t(9;22)(q34;q11)(1.7%); t(14;17)(q32;q11.2)(0.5%); inv(16)(p13;q22)(1.7%); 11q23 rearrangements (4%); monosomy 7 (2.2%) and 22 (1.1%); deletion of 9q (q22q34) (5.1%), 5q (q13q33) (0.5%) and 13q (q13q31) (0.5%); common trisomies like +8 (5.6%), +16 (1.7%), +22 (1.1%), +21 (0.5%), +13 (0.5%), +11 (0.5%), +3 (0.5%); hyperdiploidy (3.4%); hypodiploidy (1.1%); complex karyotype (4%); and other structural abnormalities (4.5%). Apart from these, three novel chromosomal abnormalities viz. t(8;18), t(7;14), t(13;15) were observed in the current study population. Conclusion: This study confirms that the incidence of chromosomal abnormalities varies considerably. Comparatively, the incidence t(15;17), and del9q is higher, while that of −5/del5q, −7/del7q and inv (16) were lower in our population. Similarly, the frequency of other recurrent FAB associated abnormalities viz. 11qabn was comparable to previous reports. Furthermore, ongoing cytogenetic studies are warranted in larger groups of AML cases to identify newly acquired chromosomal aberrations that may aid in cloning novel genes involved in the neoplastic process, ultimately helping in the development of targeted therapeutic drugs.     

T(1;21;8)(p34;q22;q22): a novel variant of t(8;21) in acute myeloblastic leukemia with maturation

The complex variants of t(8;21) involving chromosomes 8 and 21 as well as another chromosome account for approximately 3% of acute myeloid leukemia patients. We report here a 30-year-old male patient with AML-M2. Fluorescence in situ hybridization analysis using dual-color fluorescence ETO and AML1 probes located at 8q22 and 21q22 respectively showed an AML1/ETO fusion signal on the derivative chromosome 8. Whole chromosome painting probes were used for chromosome 1, 8 and 21 and revealed a three-way translocation (1;21;8)(p34 ~ p35;q22;q22). Involvement of chromosome region 1p34 has never been reported earlier, although region 1p35 as a variant in AML with t(8;21) has been reported with an AML1/ETO fusion signal on the 1p35 rather than der(8). In conclusion, combining conventional karyotype, FISH or RT-PCR analyses are a rational strategy for the identification of the complex variants of t(8;21) translocation which could be critical events responsible for leukemogenesis.     

Specific chromosomal aberrations in de novo acute myeloid leukemia: A comparative analysis of results with a report of three novel chromosomal rearrangements t(7;14)(q35;q13), t(8;18)(p11.2;q12), t(13;15) in Indian population

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with regard to morphology, immunophenotype, and genetic rearrangements. Multiple recurrent chromosomal aberrations have been identified by conventional cytogenetic analysis, which is now widely recognized as one of the most important diagnostic and prognostic determinants in AML. Method: Conventional cytogenetic analysis was done on 200 de novo AML subjects. Results: Of these, 176 (88%) were successfully karyotyped and 24 (12%) showed culture failure. Among the176 subjects, 101 (57.4%) were abnormal and 75 (42.6%) showed an apparently normal karyotype. The various aberrations observed were t(8;21)(q22;q22) (5.2%); t(15;17) (q22;q11-21) (9%); t(9;22)(q34;q11)(1.7%); t(14;17)(q32;q11.2)(0.5%); inv(16)(p13;q22)(1.7%); 11q23 rearrangements (4%); monosomy 7 (2.2%) and 22 (1.1%); deletion of 9q (q22q34) (5.1%), 5q (q13q33) (0.5%) and 13q (q13q31) (0.5%); common trisomies like +8 (5.6%), +16 (1.7%), +22 (1.1%), +21 (0.5%), +13 (0.5%), +11 (0.5%), +3 (0.5%); hyperdiploidy (3.4%); hypodiploidy (1.1%); complex karyotype (4%); and other structural abnormalities (4.5%). Apart from these, three novel chromosomal abnormalities viz. t(8;18), t(7;14), t(13;15) were observed in the current study population. Conclusion: This study confirms that the incidence of chromosomal abnormalities varies considerably. Comparatively, the incidence t(15;17), and del9q is higher, while that of −5/del5q, −7/del7q and inv (16) were lower in our population. Similarly, the frequency of other recurrent FAB associated abnormalities viz. 11qabn was comparable to previous reports. Furthermore, ongoing cytogenetic studies are warranted in larger groups of AML cases to identify newly acquired chromosomal aberrations that may aid in cloning novel genes involved in the neoplastic process, ultimately helping in the development of targeted therapeutic drugs.     

Variant Philadelphia translocations in chronic myeloid leukemia: correlation with cancer breakpoints, fragile sites and oncogenes

Four cases of variant Philadelphia (Ph1) translocations were found in 72 patients (5.5%) with Ph1-positive chronic myeloid leukemia (CML). One previously unreported case was a simple variant translocation, namely, 46,XY,t(11;17)(q13;p13),t(17;22)(q25;q22); 46,XY,t(1;21)(q32;q11),t(11;17)(q13;p13), t(17;22)(q25;q11). Complex variant translocations were observed in three cases, namely, 46,XY,t(5;9;22)(q31;q34;q11),46,XX,t(8;9;22) (q22;q34;q11) and 46,XX,t(9;15;22) (q34;q15;q11). The chromosomal breakpoints in the cases of variant Ph1 translocations were the following: 1q32, 5q31, 8q22, 11q13, 15q15, 17p13, 17q25 and 21q11. Eight of the eight (100%) breakpoints were located in Giemsa-negative bands. Furthermore, seven of the eight (87%) variant Ph1 breakpoints correspond to the breakpoints present in consistent cancer arrangements. Three of the eight (38%) correspond to fragile sites and four of the eight (50%) correspond to oncogenes.     

伴有t(8;21)变异易位的急性髓系白血病患儿二例遗传学研究

 【摘要】　目的　报道2例分别伴有t(8;20)(q22;q13)和t(1;8;21) (q32;q22;q22)的t(8;21)变异易位的M2型急性髓系白血病（AML-M2）。方法　骨髓细胞短期培养法制备染色体标本,应用反带和吉姆萨显带技术进行核型分析;双色双融合AML1-ETO探针进行间期及中期双色荧光原位杂交（D-FISH）检测AML1-ETO融合信号;多重巢式反转录-聚合酶链反应（ RT-PCR）技术检测AML1-ETO融合基因转录本。结果　例1 核型为45,X,-Y, t (8;20)(q22;q13) [12]／46,XY[3],例2 核型为46,XX,t(1;8;21)(q32;q22;q22)[18]／46,XX[2];间期和中期FISH证实了AML1-ETO融合基因和变异易位的存在;多重巢式RT-PCR检测到AML1-ETO融合基因转录本。结论　t(8;20)(q22;q13)和t(1;8;21)(q32;q22;q22)实质上都是t(8;21)的变异型易位;核型分析联合D-FISH、多重巢式RT-PCR对确定伴有变异型t(8;21)易位的AML患者的性质和预后是重要的。     

Hemophagocytosis by leukemic blasts in 7 acute myeloid leukemia cases with t(16;21)(p11;q22): common morphologic characteristics for this type of leukemia

BACKGROUND: In a previous study of a case of acute megakaryoblastic leukemia with t(16;21)(p11;q22), which displayed hemophagocytosis by leukemic blasts, the authors mentioned that the same type of morphology had been cited in the literature for 4 other cases of acute myeloid leukemia (AML) with the same translocation. This observation prompted the authors to examine more cases of AML with t(16;21)(p11;q22) for this morphology. METHODS: The authors reviewed bone marrow smears for the presence of hemophagocytosis in 7 patients with AML identified as having t(16;21)(p11;q22). RESULTS: The leukemias belonged to the FAB-M1/M7 (n = 5), M5b (n = 2), and contained phagocytic blasts in various percentages (< 0.2-36.7%). The blasts contained either single or multiple cytoplasmic vacuoles, in some of which the phagosomes were visible. The engulfed hemopoietic cells (red cells, erythroblasts, lymphocytes, and thrombocytes) were also noted in their cytoplasm. These observations confirmed that hemophagocytosis by leukemic blasts is a common and characteristic feature of this type of leukemia. CONCLUSIONS: The study of 12 cases (the 7 cases described here and the previous 5 cases) strongly supports the hypothesis that hemophagocytosis by leukemic blasts is common and characteristic in this type of leukemia, which may be related to the specific chromosome aberration of t(16;21)(p11;q22).     

11例t(16;21)(p11;q22)急性髓系白血病病例报告并文献复习

目的:探讨11例伴t(16;21)(p11;q22)染色体易位的急性髓系白血病（acute myeloid leukemia,AML)患者的临床和实验室特点。方法:回顾性分析2007年07月至2022年03月我院收治的11例t((16;21)(p11;q22)染色体易位的AML患者临床及实验室特征并复习相关文献。结果:11例t(16;21)(p11;q22)染色体易位的白血病均为AML,FAB分型:M2型4例,M4型1例,M5型3例,AML(非M3)型3例;其中男5例,女6例。染色体R显带分析11例均可见到t(16;21)(p11;q22)染色体易位,其中9例伴有附加染色体异常。融合基因TLS/FUS-ERG检测了9例均为阳性。免疫表型除表达髓系CD34、CD117、CD33、CD13、CD38外,均表达CD56。化疗1个周期后完全缓解7例。结论:t(16;21)(p11;q22)染色体易位是一种少见的重现性染色体异常,该易位产生TLS/FUS-ERG融合基因,免疫学检测多伴CD56阳性,以AML中M2/M5型多见,化疗1个周期大部分可完全缓解,但短期内易复发,预后不良。     

Clinical significance of the most common chromosome translocations in adult acute myeloid leukemia

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.     

Aml1/ETO and Pml/RARA rearrangements in a case of AML-M2 acute myeloblastic leukemia with t(15;17)

We report a case of acute myeloid leukemia FAB-type 2 with a translocation t(15;17)(q22;q12) On the basis of the cytological findings, a translocation t(8;21)(q22;q22) was suspected. FISH analyses using specific probes for t(15;17) and t(8;21) detected both PML/RARalpha and AML1/ETO rearrangements in a few percentage of cells. This case demonstrates the complexities that may occur between cytology and cytogenetic findings and the usefulness of FISH methods to detect an AML1/ETO rearrangement only suspected by cytological examination of bone marrow smears.     

Three way translocation in a new variant of t(8;21) acute myeloid leukemia involving Xp22

The t(8;21)(q22;q22) is one of the most frequent chromosomal abnormality associated with acute myeloid leukemia (AML) M2 sub type. The additional chromosomal abnormalities including structural and numerical are frequently reported with the translocation, t (8;21)(q22;q22). We report a case of AML-M2 with t(X;8;21)(p22;q22;q22) associated with loss of Y chromosome. Using a dual color fluorescence in situ hybridization (FISH) analysis with ETO and AML1 probes, we demonstrated an ETO/AML1 fusion signal on the derivative chromosome 8 and one ETO signal on derivative Chromosome Xp22. The patient did not respond to therapy and follow-up of cytogenetics revealed same chromosome abnormality. Hence, this three way translocation involving X chromosome might be associated with poor prognosis.