The associations of cytogenetics with complete remission (CR) rates, overall survival (OS), and outcomes after CR were studied in 609 previously untreated AML patients younger than 56 years old in a clinical trial comparing 3 intensive postremission therapies: intensive chemotherapy, autologous transplantation (ABMT), or allogeneic bone marrow transplantation (alloBMT) from matched related donors. Patients were categorized into favorable, intermediate, unfavorable, and unknown cytogenetic risk groups based on pretreatment karyotypes. CR rates varied significantly (P < .0001) among the 4 groups: favorable, 84% (95% confidence interval [CI], 77%-90%); intermediate, 76% (CI, 71%-81%); unfavorable, 55% (CI, 48%-63%); and unknown, 54% (CI, 33%-74%). There was similar significant heterogeneity of OS (P < .0001), with the estimated relative risk of death from any cause being 1.50 (CI, 1.10-2.05), 3.33 (CI, 2.43-4.55), and 2.66 (CI, 1.59-4.45) for the intermediate, unfavorable, and unknown risk groups, respectively, compared with the favorable group. In multivariate analyses, the effects of cytogenetic risk status on CR rate and OS could not be explained by other patient or disease characteristics. Among postremission patients, survival from CR varied significantly among favorable, intermediate, and unfavorable groups (P = .0003), with significant evidence of interaction (P = .017) between the effects of treatment and cytogenetic risk status on survival. Patients with favorable cytogenetics did significantly better following ABMT and alloBMT than with chemotherapy alone, whereas patients with unfavorable cytogenetics did better with alloBMT. Cytogenetic risk status is a significant factor in predicting response of AML patients to therapy; however, to tighten treatment correlates within genetically defined AML subsets, a significantly larger leukemia cytogenetic database is warranted.

IntroductionThe myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem-cell disorders characterized by cytopenias and frequent leukemic progression. MDS constitutes a prototype of age-related malignancy, with a prevalence in the United States that may be more than 100 000. 1 Its incidence in the United States, estimated to be more than 10 000 yearly, is likely to further increase due to the greater life expectancy of the general population (http://www.census.gov/).Chromosomal aberrations can be detected by metaphase cytogenetics (MC) in approximately 50% of MDS patients and are responsible for some of the observed clinical diversity. Based on the experience that certain chromosomal lesions have a major impact on survival in MDS, 2-5 cytogenetic results were included in The International Prognostic Scoring System (IPSS), the most commonly applied prognostic algorithm for MDS. Moreover, recent studies demonstrate that MDS patients with certain cytogenetic abnormalities may be candidates for targeted therapies. For example, lenalidomide results in a high remission rate in MDS patients with 5q-abnormalities. 6,7 High-resolution single nucleotide polymorphisms arrays (SNP-A) can be applied in karyotypic analysis. SNP-A-based karyotyping does not depend upon the availability of live, dividing cells, and consequently can yield results when routine MC is not informative. Moreover, due to the higher resolution of SNP-A as compared with MC, smaller, previously cryptic deletions and duplications can be detected. A major advantage of this technology over MC is its ability to identify loss of heterozygosity (LOH) that occurs without concurrent changes in the gene copy number (CN). Such defects are consistent with acquired uniparental disomy (UPD) and can be attributed to errors in mitotic recombination occurring in somatic cells. Acquired segmental UPD is being increasingly recognized in a variety of neoplasms. 8,9 UPD has been described in chronic lymphocytic leukemia 10 and polycythemia vera as a mechanism leading to homozygosity for the Jak2 mutation. 11 Recently, an extensive study of acute lymphoblastic leukemia using SNP-A revealed chromosomal deletions and amplifications, many of them involving genes encoding principal regulators of B-lymphocyte development. 12 SNP-A also has been used for detecting genomic lesions in smaller case series of myeloma, 13 leukemias, 14-16 and lymphoma. 17 Initially using 50K arrays, we have demonstrated the potential diagnostic value of this technology, in a smaller cohort of myelodysplastic syndrome (MDS) patients. 18 This preliminary study demonstrated frequent detection of UPD in MDS. Subsequent larger studies limited to low-risk MDS showed similar results. 19 MDS is a particularly suitable target for demonstrating the use of SNP-A, as acquired cytogenetic abnormalities are relatively frequent and mostly unbalanced. 20 Using this disease as a model, we tested the hypothesis that high-density SNP-A can complement routine MC and enhance its diagnostic re...

The associations of cytogenetics with complete remission (CR) rates, overall survival (OS), and outcomes after CR were studied in 609 previously untreated AML patients younger than 56 years old in a clinical trial comparing 3 intensive postremission therapies: intensive chemotherapy, autologous transplantation (ABMT), or allogeneic bone marrow transplantation (alloBMT) from matched related donors. Patients were categorized into favorable, intermediate, unfavorable, and unknown cytogenetic risk groups based on pretreatment karyotypes. CR rates varied significantly (P < .0001) among the 4 groups: favorable, 84% (95% confidence interval [CI], 77%-90%); intermediate, 76% (CI, 71%-81%); unfavorable, 55% (CI, 48%-63%); and unknown, 54% (CI, 33%-74%). There was similar significant heterogeneity of OS (P < .0001), with the estimated relative risk of death from any cause being 1.50 (CI, 1.10-2.05), 3.33 (CI, 2.43-4.55), and 2.66 (CI, 1.59-4.45) for the intermediate, unfavorable, and unknown risk groups, respectively, compared with the favorable group. In multivariate analyses, the effects of cytogenetic risk status on CR rate and OS could not be explained by other patient or disease characteristics. Among postremission patients, survival from CR varied significantly among favorable, intermediate, and unfavorable groups (P = .0003), with significant evidence of interaction (P = .017) between the effects of treatment and cytogenetic risk status on survival. Patients with favorable cytogenetics did significantly better following ABMT and alloBMT than with chemotherapy alone, whereas patients with unfavorable cytogenetics did better with alloBMT. Cytogenetic risk status is a significant factor in predicting response of AML patients to therapy; however, to tighten treatment correlates within genetically defined AML subsets, a significantly larger leukemia cytogenetic database is warranted.

We have identified a gene at 11q23, telomeric to MLL, that encodes a guanine nucleotide exchange factor (GEF). This gene is transcribed into a 9.5-kb mRNA containing a 4.6-kb ORF. By Northern analysis, it was found to be expressed in all human tissues examined including peripheral blood leukocytes, spleen, prostate, testis, ovary, small intestine, colon, and minimally in thymus. Analysis of the predicted protein sequence indicates that it has strong homology to several members of the family of Rho GEFs that includes such oncogenes as Dbl, Vav, Tiam, and Bcr. A patient with primary acute myeloid leukemia (AML) and a karyotype of 51,XY,؉8,؉19,؉3mar was found to have the 5 end of MLL at exon 6 fused in-frame with the 3 end of almost the entire ORF of this gene, which we named LARG for leukemia-associated Rho GEF. Transcriptional orientation of both genes at 11q23 is from centromere to telomere, consistent with other data that suggest the MLL-LARG fusion resulted from an interstitial deletion rather than a balanced translocation. LARG does not appear to have any homology with other MLL partner genes reported thus far. Thus, LARG represents an additional member of the GEF family and a novel MLL fusion partner in acute myeloid leukemia.LARG ͉ Dbl protein ͉ gene rearrangements