G2Cdb::Human Disease report

Disease id
D00000103
Name
Leukaemia
Nervous system disease
no

Genes (2)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002371 CALM1
calmodulin 1 (phosphorylase kinase, delta)
Y (10221337) Translocation (T) Y
G00002371 CALM1
calmodulin 1 (phosphorylase kinase, delta)
Y (16956826) Translocation fusion (with another gene) (TF) Y
G00002371 CALM1
calmodulin 1 (phosphorylase kinase, delta)
Y (16921363) Translocation fusion (with another gene) (TF) Y
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (15968309) Translocation fusion (with another gene) (TF) Y

References

  • Dual-color split signal fluorescence in situ hybridization assays for the detection of CALM/AF10 in t(10;11)(p13;q14-q21)-positive acute leukemia.

    La Starza R, Crescenzi B, Krause A, Pierini V, Specchia G, Bardi A, Nieddu R, Ariola C, Nanni M, Diverio D, Aventin A, Sborgia M, Martelli MF, Bohlander SK and Mecucci C

    Hematology and Bone Marrow Transplantation Unit, Policlinico Monteluce, via Brunamonti, 06122 Perugia, Italy.

    We developed dual-color split fluorescence in situ hybridization (FISH) assays to detect AF10 and/or CALM rearrangements. Among nine cases of acute leukemia with translocation breakpoints at 10p13 and 11q14-21, a CALM/AF10 rearrangement was found in seven and was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) in all. In 2/7 cases, FISH detected CALM/AF10 in extramedullary leukemic infiltrations in the mediastinum and breast. As expected, FISH was less sensitive than RT-PCR for disease monitoring of CALM-AF10 positive cases. This new FISH assay reliably discriminates between MLL/AF10 and CALM/AF10 genomic rearrangements, identifies variant and complex CALM/AF10 translocations and detects the CALM/AF10 rearrangement in extramedullary leukemic infiltrations.

    Haematologica 2006;91;9;1248-51

  • Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L.

    Okada Y, Jiang Q, Lemieux M, Jeannotte L, Su L and Zhang Y

    Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.

    Chromosomal translocation is a common cause of leukaemia and the most common chromosome translocations found in leukaemia patients involve the mixed lineage leukaemia (MLL) gene. AF10 is one of more than 30 MLL fusion partners in leukaemia. We have recently demonstrated that the H3K79 methyltransferase hDOT1L contributes to MLL-AF10-mediated leukaemogenesis through its interaction with AF10 (ref. 5). In addition to MLL, AF10 has also been reported to fuse to CALM (clathrin-assembly protein-like lymphoid-myeloid) in patients with T-cell acute lymphoblastic leukaemia (T-ALL) and acute myeloid leukaemia (AML). Here, we analysed the molecular mechanism of leukaemogenesis by CALM-AF10. We demonstrate that CALM-AF10 fusion is both necessary and sufficient for leukaemic transformation. Additionally, we provide evidence that hDOT1L has an important role in the transformation process. hDOT1L contributes to CALM-AF10-mediated leukaemic transformation by preventing nuclear export of CALM-AF10 and by upregulating the Hoxa5 gene through H3K79 methylation. Thus, our study establishes CALM-AF10 fusion as a cause of leukaemia and reveals that mistargeting of hDOT1L and upregulation of Hoxa5 through H3K79 methylation is the underlying mechanism behind leukaemia caused by CALM-AF10 fusion.

    Funded by: NHLBI NIH HHS: HL72240, R21 HL072240; NIAID NIH HHS: AI48407, R01 AI048407, R01 AI077454, R01 AI080432, R56 AI048407; NIGMS NIH HHS: GM68804, R01 GM068804

    Nature cell biology 2006;8;9;1017-24

  • [Role of molecular screening for common fusion genes in the diagnosis and classification of leukemia].

    Zhu YL, Zhang Y, Zhu P, Yang Y, Du JW and Liu J

    Department of Haematology, Peking University First Hospital, Beijing 100034, China.

    Objective: To assess the value of common fusion genes analysis in the diagnosis and classification of leukemia by multiplex RT-PCR.

    Methods: The multiplex RT-PCR, including 8 parallel PCR reactions, could screen 86 mRNA breakpoints or splice variants at the same time, which was important for the diagnosis and prognosis of leukemia. Bone marrow samples from 161 cases of leukemia and 8 cases of myelodysplastic syndrome (MDS) were involved in the study. The distribution of common fusion genes in leukemia was analyzed by the method mentioned above in combination with clinical and morphological features.

    Results: Ten fusion genes were detected in 115 cases of leukemia, including AML1/ETO, PML/RAR alpha, PLZF/RAR alpha, dupMLL, MLL/AF6, MLL/AF10, CBFbeta/MYH11, BCR/ABL, Hox11, and EVI1 BCR/ABL was positive in all the 52 cases of chronic myeloid leukemia; PML/RAR alpha was found in 21 of 25 acute promyelocytic leukemia (APL), and PLZF/RAR alpha was detected in one case of APL. Sixteen cases of 17 AML1/ETO-positive acute leukemia (AL) belonged to FAB-M2 subtype, and one case was mixed leukemia. Three of 4 AL cases carrying CBFbeta/MYH11 were M4 subtype, and one was M5 subtype. MLL aberrations were found in 16 AL, in which all MLL/AF6 translocation existed in M5 subtype with classic monoblastic characters. Furthermore, BCR/ABL was detected in 5 acute lymphoblastic leukemia (ALL) cases. Fusion genes were also found in 2 MDS cases, of which AML1/ETO positive-MDS-RAEB progressed to AML rapidly.

    Conclusion: Screening of common fusion genes by multiplex RT-PCR is an important tool which could provide useful and reliable molecular genetic information for the diagnosis and treatment of leukemia.

    Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 2005;37;3;236-9

  • Mixed-lineage leukemia with t(10;11)(p13;q21): an analysis of AF10-CALM and CALM-AF10 fusion mRNAs and clinical features.

    Kumon K, Kobayashi H, Maseki N, Sakashita A, Sakurai M, Tanizawa A, Imashuku S and Kaneko Y

    Department of Cancer Chemotherapy, Saitama Cancer Center Hospital, Ina, Japan.

    A fusion transcript of AF10 and CALM was isolated recently from the U937 cell line with t(10;11)(p13;q21). We performed reverse transcription-polymerase chain reaction and sequencing analysis on the t(10;11) leukemia samples obtained from four patients and one cell line, and we identified reciprocal fusion transcripts of AF10 and CALM in all the samples. The fusion transcripts in the five samples showed four different breakpoints in AF10 and three different breakpoints in CALM. In addition, the fusion transcripts in one sample showed a nucleotide sequence deletion in AF10, and those in two samples showed a nucleotide sequence deletion in CALM; the deletions were thought to be caused by alternative splicing. The variety of breakpoints and splice sites in the two genes resulted in five different-sized AF10-CALM mRNAs and in four different-sized CALM-AF10 mRNAs. Clinical features of 11 patients, including 6 of our own and 5 reported by others, in whom the fusion of AF10 and CALM was identified, are characterized by young age of the patients, mixed-lineage immunophenotype with coexpression of T-cell and myeloid antigens, frequent occurrence of a mediastinal mass, and poor clinical outcome.

    Genes, chromosomes & cancer 1999;25;1;33-9

Literature (4)

Pubmed - human_disease

  • Dual-color split signal fluorescence in situ hybridization assays for the detection of CALM/AF10 in t(10;11)(p13;q14-q21)-positive acute leukemia.

    La Starza R, Crescenzi B, Krause A, Pierini V, Specchia G, Bardi A, Nieddu R, Ariola C, Nanni M, Diverio D, Aventin A, Sborgia M, Martelli MF, Bohlander SK and Mecucci C

    Hematology and Bone Marrow Transplantation Unit, Policlinico Monteluce, via Brunamonti, 06122 Perugia, Italy.

    We developed dual-color split fluorescence in situ hybridization (FISH) assays to detect AF10 and/or CALM rearrangements. Among nine cases of acute leukemia with translocation breakpoints at 10p13 and 11q14-21, a CALM/AF10 rearrangement was found in seven and was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) in all. In 2/7 cases, FISH detected CALM/AF10 in extramedullary leukemic infiltrations in the mediastinum and breast. As expected, FISH was less sensitive than RT-PCR for disease monitoring of CALM-AF10 positive cases. This new FISH assay reliably discriminates between MLL/AF10 and CALM/AF10 genomic rearrangements, identifies variant and complex CALM/AF10 translocations and detects the CALM/AF10 rearrangement in extramedullary leukemic infiltrations.

    Haematologica 2006;91;9;1248-51

  • Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L.

    Okada Y, Jiang Q, Lemieux M, Jeannotte L, Su L and Zhang Y

    Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.

    Chromosomal translocation is a common cause of leukaemia and the most common chromosome translocations found in leukaemia patients involve the mixed lineage leukaemia (MLL) gene. AF10 is one of more than 30 MLL fusion partners in leukaemia. We have recently demonstrated that the H3K79 methyltransferase hDOT1L contributes to MLL-AF10-mediated leukaemogenesis through its interaction with AF10 (ref. 5). In addition to MLL, AF10 has also been reported to fuse to CALM (clathrin-assembly protein-like lymphoid-myeloid) in patients with T-cell acute lymphoblastic leukaemia (T-ALL) and acute myeloid leukaemia (AML). Here, we analysed the molecular mechanism of leukaemogenesis by CALM-AF10. We demonstrate that CALM-AF10 fusion is both necessary and sufficient for leukaemic transformation. Additionally, we provide evidence that hDOT1L has an important role in the transformation process. hDOT1L contributes to CALM-AF10-mediated leukaemic transformation by preventing nuclear export of CALM-AF10 and by upregulating the Hoxa5 gene through H3K79 methylation. Thus, our study establishes CALM-AF10 fusion as a cause of leukaemia and reveals that mistargeting of hDOT1L and upregulation of Hoxa5 through H3K79 methylation is the underlying mechanism behind leukaemia caused by CALM-AF10 fusion.

    Funded by: NHLBI NIH HHS: HL72240, R21 HL072240; NIAID NIH HHS: AI48407, R01 AI048407, R01 AI077454, R01 AI080432, R56 AI048407; NIGMS NIH HHS: GM68804, R01 GM068804

    Nature cell biology 2006;8;9;1017-24

  • [Role of molecular screening for common fusion genes in the diagnosis and classification of leukemia].

    Zhu YL, Zhang Y, Zhu P, Yang Y, Du JW and Liu J

    Department of Haematology, Peking University First Hospital, Beijing 100034, China.

    Objective: To assess the value of common fusion genes analysis in the diagnosis and classification of leukemia by multiplex RT-PCR.

    Methods: The multiplex RT-PCR, including 8 parallel PCR reactions, could screen 86 mRNA breakpoints or splice variants at the same time, which was important for the diagnosis and prognosis of leukemia. Bone marrow samples from 161 cases of leukemia and 8 cases of myelodysplastic syndrome (MDS) were involved in the study. The distribution of common fusion genes in leukemia was analyzed by the method mentioned above in combination with clinical and morphological features.

    Results: Ten fusion genes were detected in 115 cases of leukemia, including AML1/ETO, PML/RAR alpha, PLZF/RAR alpha, dupMLL, MLL/AF6, MLL/AF10, CBFbeta/MYH11, BCR/ABL, Hox11, and EVI1 BCR/ABL was positive in all the 52 cases of chronic myeloid leukemia; PML/RAR alpha was found in 21 of 25 acute promyelocytic leukemia (APL), and PLZF/RAR alpha was detected in one case of APL. Sixteen cases of 17 AML1/ETO-positive acute leukemia (AL) belonged to FAB-M2 subtype, and one case was mixed leukemia. Three of 4 AL cases carrying CBFbeta/MYH11 were M4 subtype, and one was M5 subtype. MLL aberrations were found in 16 AL, in which all MLL/AF6 translocation existed in M5 subtype with classic monoblastic characters. Furthermore, BCR/ABL was detected in 5 acute lymphoblastic leukemia (ALL) cases. Fusion genes were also found in 2 MDS cases, of which AML1/ETO positive-MDS-RAEB progressed to AML rapidly.

    Conclusion: Screening of common fusion genes by multiplex RT-PCR is an important tool which could provide useful and reliable molecular genetic information for the diagnosis and treatment of leukemia.

    Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 2005;37;3;236-9

  • Mixed-lineage leukemia with t(10;11)(p13;q21): an analysis of AF10-CALM and CALM-AF10 fusion mRNAs and clinical features.

    Kumon K, Kobayashi H, Maseki N, Sakashita A, Sakurai M, Tanizawa A, Imashuku S and Kaneko Y

    Department of Cancer Chemotherapy, Saitama Cancer Center Hospital, Ina, Japan.

    A fusion transcript of AF10 and CALM was isolated recently from the U937 cell line with t(10;11)(p13;q21). We performed reverse transcription-polymerase chain reaction and sequencing analysis on the t(10;11) leukemia samples obtained from four patients and one cell line, and we identified reciprocal fusion transcripts of AF10 and CALM in all the samples. The fusion transcripts in the five samples showed four different breakpoints in AF10 and three different breakpoints in CALM. In addition, the fusion transcripts in one sample showed a nucleotide sequence deletion in AF10, and those in two samples showed a nucleotide sequence deletion in CALM; the deletions were thought to be caused by alternative splicing. The variety of breakpoints and splice sites in the two genes resulted in five different-sized AF10-CALM mRNAs and in four different-sized CALM-AF10 mRNAs. Clinical features of 11 patients, including 6 of our own and 5 reported by others, in whom the fusion of AF10 and CALM was identified, are characterized by young age of the patients, mixed-lineage immunophenotype with coexpression of T-cell and myeloid antigens, frequent occurrence of a mediastinal mass, and poor clinical outcome.

    Genes, chromosomes & cancer 1999;25;1;33-9

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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