1: Chem Biol Interact. 2005 May 30;153-154:187-95. Epub 2005 Apr 13. Therapy-related myeloid leukaemia: a model for leukemogenesis in humans. Larson RA, Le Beau MM. Section of Hematology/Oncology, Department of Medicine and Cancer Research Center, University of Chicago, MC-2115, 5341 S. Maryland Avenue, Chicago, IL 60637, USA. rlarson@medicine.bsd.uchicago.edu Therapy-related myeloid leukemia (t-AML) is a distinctive clinical syndrome occurring after exposure to chemotherapy (CT) or radiotherapy (RT). We studied 306 consecutive patients referred to the University of Chicago with cytogenetic analyses. Since 1972, 141 males and 165 females with a median age of 51 years (range: 3-83 years) at primary diagnosis and 58 years (range: 6-86 years) at secondary diagnosis were analyzed. Patients had received various cytotoxic agents including alkylating agents (240 patients, 78%) and topoisomerase II inhibitors (115 patients, 39%). One hundred and twenty-one (40%) had received CT alone, 43 (14%) had received RT alone, and 139 (45%) had received both modalities. At diagnosis of t-AML, 282 (92%) had clonal abnormalities involving chromosome 5 (n=63), chromosome 7 (n=85), both chromosomes 5 and 7 (n=66), recurring balanced rearrangements (n=31), or other clonal abnormalities (n=39); 24 had a normal karyotype. Abnormalities of chromosomes 5 and/or 7 accounted for 76% of all cases with an abnormal karyotype. Seventeen patients had developed t-AML after autologous stem cell transplantation, but no unique pattern of cytogenetic abnormalities was observed. Patients presenting with acute leukemia were more likely to have a balanced rearrangement than those presenting with myelodysplasia (28% versus 4%, p<0.0001). Shorter latency was observed for patients with balanced rearrangements (median: 28 months versus 67 months; p<0.0001). Median survival after diagnosis of t-AML was 8 months; survival at 5 years was less than 10%. To gain insights into the molecular basis of this disease, we performed gene expression profiling of CD34+ hematopoietic progenitor cells from t-AML patients. We found distinct subtypes of t-AML that have characteristic gene expression patterns. Common to each of the subgroups are gene expression patterns typical of arrested differentiation in early progenitor cells. Leukemias with a -5/del(5q) have a higher expression of genes involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), and loss of expression of the gene encoding interferon consensus sequence-binding protein (ICSBP). A second subgroup of t-AML is characterized by down-regulation of transcription factors involved in early hematopoiesis (TAL1, GATA1, and EKLF) and overexpression of proteins involved in signaling pathways in myeloid cells (FLT3) and cell survival (BCL2). Establishing the molecular pathways involved in t-AML may facilitate the identification of selectively expressed genes that can be exploited for the development of targeted therapies. PMID: 15935816 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 2: Ann Hematol. 2003 Aug;82(8):506-10. Epub 2003 Jun 21. Terminal differentiation in vitro of patient-derived post-TMD megakaryoblastic AML cells. Classen CF, Gnekow A, Debatin KM. University Children's Hospital Ulm, Prittwitzstrasse 43, 89070, Ulm, Germany. carl.classen@medizin.uni-ulm.de Differentiation induction is a therapeutic principle in acute promyelocytic leukemia (AML) using all- trans retinoic acid. In cell lines with properties of AML M6/M7 (K562 and CMK), differentiation towards megakaryopoietic and erythropoietic phenotypes can be induced in vitro. Transitory myeloproliferative disorder (TMD) is a self-limited disorder of newborn infants with Down syndrome, phenotypically resembling acute myeloid leukemia of megakaryoblastic lineage. Despite spontaneous disappearance of blasts from blood and bone marrow, in about 10% of the patients, overt acute megakaryoblastic leukemia (AML M7) develops up to 4 years later. Recently, mutations of the GATA1 transcription factor have been identified in the megakaryoblastic leukemia of Down syndrome. Here, we studied cells from a patient suffering from megakaryoblastic AML at the age of 2.5 years after spontaneous remission of neonatal TMD. In vitro, terminal differentiation towards a megakaryocyte-like phenotype could be induced by phorbol myristate acetate (PMA), with typical morphological features, upregulation of platelet-specific and downregulation of erythroid antigens, going along with downregulation of c-myc. Whether spontaneous resolution of TMD is a process due to terminal differentiation is still open; however, here we give evidence that in vitro differentiation can be induced even in blasts deriving from an overt AML French-American-British (FAB) M7 after TMD. Publication Types: Case Reports PMID: 12910377 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 3: Med Sci (Paris). 2003 Feb;19(2):201-10. [Oncogenes and leukemia: history and perspectives] [Article in French] Gisselbrecht S. Departement d'Hematologie de l'Institut Cochin, Inserm U.567, Cnrs UMR 8104, Batiment Gustave Roussy, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France. gisselbrecht@cochin.inserm.fr Oncogenes involved in the development of hematological malignancies were first discovered through the study of experimental leukemias induced in animals by retroviruses. The discovery that some of these genes were located at the breakpoints of chromosome rearrangements in human malignancies, such as the MYC gene in Burkitt's lymphoma and the ABL gene in chronic myeloid leukemia (CML) has suggested that chromosome abnormalities were causally implicated in the pathogenesis of human diseases. Numerous nonrandom somatically acquired chromosomal translocations or inversions have been identified in human leukemias. The molecular cloning of the genes located at the breakpoints of these rearrangements allowed to identify more than 100 new oncogenes, the products of which affect normal programs of cell proliferation, differentiation and survival. Chromosome translocations can lead to the deregulated expression of a normal gene product, but in most cases of leukemia, chromosome rearrangements result in the expression of a chimeric fusion protein. Oncogene products associated with acute leukemias are often transcription factors while tyrosine kinases and antiapoptotic proteins are more commonly activated or overexpressed in chronic leukemias and in lymphomas. Recent data indicated that gene rearrangements were not the sole gene alterations occurring in human leukemia since point mutations could also affect the function of transcription factors playing a key role in hematopoiesis such as C/EBP alpha, GATA1 and AML1. But the most exciting finding was the discovery of activating point mutations in tyrosine kinase receptors such as FLT3 and c-KIT in acute leukemia. Treatment of leukemia could therefore benefit from new therapeutic approaches targeting the function of specific oncogene products as already demonstrated for CML and acute promyelocytic leukemia. Publication Types: Historical Article Review Review, Tutorial PMID: 12836614 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 4: Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14925-30. Epub 2002 Nov 4. Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia. Qian Z, Fernald AA, Godley LA, Larson RA, Le Beau MM. Section of Hematology/Oncology and the Cancer Research Center, University of Chicago, IL 60637, USA. zqian@medicine.bsd.uchicago.edu One of the most serious consequences of cytotoxic cancer therapy is the development of therapy-related acute myeloid leukemia (t-AML), a neoplastic disorder arising from a multipotential hematopoietic stem cell. To gain insights into the molecular basis of this disease, we performed gene expression profiling of CD34(+) hematopoietic progenitor cells from t-AML patients. Our analysis revealed that there are distinct subtypes of t-AML that have a characteristic gene expression pattern. Common to each of the subgroups are gene expression patterns typical of arrested differentiation in early progenitor cells. Leukemias with a -5/del(5q) have a higher expression of genes involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), and loss of expression of the gene encoding IFN consensus sequence-binding protein (ICSBP). A second subgroup of t-AML is characterized by down-regulation of transcription factors involved in early hematopoiesis (TAL1, GATA1, and EKLF) and overexpression of proteins involved in signaling pathways in myeloid cells (FLT3) and cell survival (BCL2). Establishing the molecular pathways involved in t-AML may facilitate the identification of selectively expressed genes that can be exploited for the development of urgently needed targeted therapies. PMID: 12417757 [PubMed - indexed for MEDLINE] ---------------------------------------------------------------