Acute multilineage (B/myeloid) leukemia with RUNX1 duplication/amplification and hypereosinophilia

A 14–year‐old girl presented with myalgias and decreased energy and was found to have a white count of 73 000 with 75% eosinophils. Flow cytometry and immunostains showed the blasts in the bone marrow expressed both myeloid and lymphoid markers. Patient was diagnosed with acute multilineage (B/Myeloid) leukemia. Genetic testing revealed four copies of the RUNX1 gene region in 25.5%, with a normal karyotype and no evidence of t(8;21) or t(12;21) by fluorescence in situ hybridization. RUNX1 translocations and amplifications have been implicated in acute myeloblastic leukemia, acute lymphoblastic leukemia, and MDS, but have not yet been seen with acute multilineage leukemia. Additionally, it is unclear what the risk stratification of this unique presentation will turn out to be.     

RUNX3、 CyclinD1在胰腺癌组织中的表达及临床意义

目的 检测RUNX3、CyclinD1蛋白在胰腺癌组织中的表达,分析其临床意义。方法 采用免疫组化SP法检测47例胰腺癌、18例胰腺囊腺瘤及12例正常胰腺组织中RUNX3和CyclinD1蛋白的表达,分析它们与临床病理参数间的关系。结果 胰腺癌、胰腺囊腺瘤和正常胰腺组织的RUNX3蛋白阳性表达率分别为57.4％(27/47)、94.4％ (17/18)、100％( 12/12);CyclinDl蛋白阳性表达率分别为72.3％ (34/47)、44.4％(8/18)、8.3％(1/12)。胰腺癌RUNX3阳性表达与患者性别、年龄无关,与胰腺癌的临床分期、淋巴结转移、分化程度呈负相关(P＜0.05)。CyclinD1阳性表达与患者性别、年龄无关,与胰腺癌临床分期、淋巴结转移、分化程度呈正相关(P＜0.05)。胰腺癌组织RUNX3与CyclinDl的表达呈负相关(r= -0.375,P=0.009)。结论 胰腺癌组织中RUNX3呈低表达,Cyclin D1呈过表达,它们均与胰腺癌的发生、发展有关。     

Acute myeloid leukemia with a RUNX1-RUNX1T1 t(1;21;8)(q21;q22;q22) novel variant: a case report and review of the literature

Variants of t(8;21)(q22;q22) account for approximately 3% of all t(8;21) in acute myeloid leukemia (AML). We report a 63-year-old female patient with AML, who showed a 3-way novel variant of t(8;21), t(1;21;8)(q21;q22;q22). She presented with gastric discomfort and splenomegaly, and her complete blood count was: white blood cell count 7.96 × 10(9)/l, with 7% blasts; hemoglobin 8.3 g/dl, and platelets 66 × 10(9)/l. Her bone marrow showed increased blasts (32.5%) with a basophilic cytoplasm, salmon-pink granules and Auer rods. Cytogenetic analysis revealed a karyotype of 46,XX,t(1;21;8)(q21;q22;q22), and fluorescence in situ hybridization confirmed a RUNX1-RUNX1T1 fusion signal on the derivative chromosome 8. After induction chemotherapy, the patient achieved complete remission and has been stable for 6 months. To the best of our knowledge, this is the first report on the novel variant of t(8;21) involving the breakpoint 1q21 and the third case with a translocation among chromosomes 1, 21 and 8. Although the clinical relevance of variant t(8;21) is still unclear, a review of 24 such cases in the literature does not imply a poorer prognosis of variant t(8;21) than of the classic t(8;21).     

t(8;21)(q22;q22) Fusion proteins preferentially bind to duplicated AML1/RUNX1 DNA-binding sequences to differentially regulate gene expression

Chromosome abnormalities are frequently associated with cancer development. The 8;21(q22;q22) chromosomal translocation is one of the most common chromosome abnormalities identified in leukemia. It generates fusion proteins between AML1 and ETO. Since AML1 is a well-defined DNA-binding protein, AML1-ETO fusion proteins have been recognized as DNA-binding proteins interacting with the same consensus DNA-binding site as AML1. The alteration of AML1 target gene expression due to the presence of AML1-ETO is related to the development of leukemia. Here, using a 25-bp random double-stranded oligonucleotide library and a polymerase chain reaction (PCR)-based DNA-binding site screen, we show that compared with native AML1, AML1-ETO fusion proteins preferentially bind to DNA sequences with duplicated AML1 consensus sites. This finding is further confirmed by both in vitro and in vivo DNA-protein interaction assays. These results suggest that AML1-ETO fusion proteins have a selective preference for certain AML1 target genes that contain multimerized AML1 consensus sites in their regulatory elements. Such selected regulation provides an important molecular mechanism for the dysregulation of gene expression during cancer development.     

Point Mutations of the RUNX1/AML1 Gene in Sporadic and Familial Myeloid Leukemias

The RUNX1/AML1 gene is known to be the most frequent target for chromosomal translocation in leukemia. In addition, recent studies have demonstrated point mutations in the RUNX1 gene as an another mode of genetic lesion resulting in leukemia. Of particular interest, sporadic point mutations of biallelic type are found in a tight association with either the acute myelogenous leukemia (AML) MO subtype or trisomy 21. Germline mutations give rise to a familial platelet disorder that results in a predisposition to acute myelogenous leukemia (FPD/AML). Most of the RUNX1 mutants were defective in DNA binding but still active in beta binding, a characteristic that is consistent with the 3-dimensional structural findings and may explain the dominant inhibitory effects. Although genuine haploinsufficiency of RUNX1 was observed in some cases, a greater majority of mutant RUNX1 proteins may also act in a dominant-negative manner, possibly creating a higher propensity for leukemia development. The stronger dominant-negative effect was also deduced to be the major mechanism of the chimeric genes created by chromosomal translocations. The decrement of RUNXI activity may be a common underlying cause for RUNX1-related leukemias. However, because these RUNX1 abnormalities per se are insufficient for leukemogenesis, cooperating genetic alteration(s) should be intensively sought for further mechanistic insights and future clinical applications.