Juvenile myelomonocytic leukemia: molecular understanding and prospects for therapy

Juvenile myelomonocytic leukemia is a rare but deadly myeloproliferative disorder of early childhood that infrequently progresses to acute leukemia. The pathogenesis of this leukemia has been linked to deregulated signal transduction, resulting in growth factor hypersensitivity. Several other myeloproliferative disorders appear to share growth factor hypersensitivity as a common pathophysiological mechanism and thus this leukemia serves as an important model. New treatment modalities, such as retinoid therapy, are emerging for juvenile myelomonocytic leukemia. Further understanding of deregulated signal transduction should pave the way for even more rationally designed therapy for this leukemia and related disorders.     

Characteristics of secondary acute nonlymphocytic leukemias. Cytological aspects (a review)

A register of 746 cases of secondary acute leukemias has been established by reviewing the literature from 1930-1980. Out of these 680 belong to acute nonlymphocytic leukemias, FAB M1-M6. Data have been subjected to a multiparameter analysis in term of previous therapy and subtype characteristics of acute nonlymphocytic leukemia (ANLL). There are indications that secondary ANLL are characterized by the preponderance of early acute myeloblastic leukemias if compared to de novo ones. Furthermore it has been shown that alkylating agents induced decidedly more acute myelomonocytic leukemias whereas irradiation tended to induce more acute myeloblastic leukemia. Since secondary acute leukemias represent a serious late consequence of alkylating agent and irradiation therapy it is high time to find new therapeutical modalities for lymphomas and to consider the withdrawal of alkylating agents from the therapy of autoimmune disorders.     

Immunophenotyping of acute non-lymphoblastic leukaemias

Using monoclonal antibodies specific for myelomonocytic cells, 40 non-lymphoblastic leukaemias were analysed applying immunostaining to cytospin preparations. Based on the reactivity patterns six groups of acute non-lymphoblastic leukaemias could be determined, mirroring the bimodal differentiation pathway of myelomonocytic cells. Comparative enzyme cytochemical analysis did not render a clear cut correlation and discrimination of the immunocytochemically defined groups. It is concluded that only the application of a broad panel of immunocytochemical and enzyme cytochemical methods allow a sound subdivision and diagnosis of acute non-lymphoblastic leukaemias.     

Myelomonocytic leukemia: clinical, cytological, and cytogenetic studies of acute, subacute, and chronic forms (author's transl)]

44 patients suffering from myelomonocytic leukemia (MML) have been observed over the last four years. They have been subclassified in acute myelomonocytic and acute monoblastic leukemias (AMML, n = 12; AMoL, n = 10), subacute myelomonocytic leukemias (SMML, n = 13), and chronic myelomonocytic leukemias (CMML, n = 9) on the basis of bone marrow cytology(blast and promonocyte counts, maturation of granulopoesis) and cytochemical findings (peroxydase and unspecific esterase reaction). This subclassification has been proved to be of prognostic relevance by its good correlation with the mean survival times (AMML : 4.5 months, AMoL : 2.4 months, SMML : 8 months, CMML : 18 months). The acute forms have been treated in general with combined cytostatic chemotherapy, whereas SMML and CMML have been treated this way only in case of progression to an acute phase. These progressions to an AMML have been observed more often and earlier in subacute forms than in chronic forms. The diagnosis of SMML and CMML is supported by the finding of sea-blue histiocytes in the bone marrow, increased lysozyme levels in serum and urine and by the absence of the Philadelphia-Chromosome.     

A novel translocation,t(9;21)(q13;q22) rearranging the RUNX1 gene in acute myelomonocytic leukemia

A novel translocation t(9;21)(q13;q22) associated with trisomy 4 has been detected in a patient with acute myelomonocytic leukemia (AML,M4) in relapse. The chromosomal translocation results in rearrangement of the RUNX1 gene at 21q22. The DNA sequence rearranged on chromosome 9 remains unidentified. The diversity of the partners involved in translocations implicating RUNX1 suggests that the functional consequences of the abnormality are more due to the truncation of RUNX1 than to the identity of its partner in the rearrangement.     

Transformation by v-myb correlates with trans-activation of gene expression.

The v-myb oncogene of avian myeloblastosis virus causes acute myelomonocytic leukemia in chickens and transforms avian myeloid cells in vitro. Its protein product p48v-myb is a nuclear, sequence-specific, DNA-binding protein which activates gene expression in transient DNA transfection studies. To investigate the relationship between transformation and trans-activation by v-myb, we constructed 15 in-frame linker insertion mutants. The 12 mutants which transformed myeloid cells also trans-activated gene expression, whereas the 3 mutants which did not transform also did not trans-activate. This implies that trans-activation is required for transformation by v-myb. One of the transformation-defective mutants localized to the cell nucleus but failed to bind DNA. The other two transformation-defective mutants localized to the cell nucleus and bound DNA but nevertheless failed to trans-activate. These latter mutants define two distinct domains of p48v-myb which control trans-activation by DNA-bound protein, one within the amino-terminal DNA-binding domain itself and one in a carboxyl-terminal domain which is not required for DNA binding.     

Acute lymphocytic and myelomonocytic leukemia associated with low platelet counts and a 21q- marker chromosome

Summary A terminal deletion of the long arm of one chromosome 21 at band q21 was found in two patients with acute leukemia and a low platelet count: one case of acute myelomonocytic leukemia and one case of acute lymphocytic leukemia. The segment deleted from chromosome 21 could not be found translocated to any other chromosome of the complement. The results indicate that the 21q- marker chromosome may be due to a true deletion and that the marker is not specific for primary thrombocythemia or other myeloproliferative disorders associated with thrombocytosis.     

Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease

Chromosomal translocations that fuse the mixed lineage leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy-related leukemias. We utilized a conditional knockin strategy to bypass the embryonic lethality caused by MLL-CBP expression and to assess the immediate effects of induced MLL-CBP expression on hematopoiesis. Within days of activating MLL-CBP, the fusion protein selectively expanded granulocyte/macrophage progenitors (GMP) and enhanced their self-renewal/proliferation. MLL-CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal gamma-irradiation or N-ethyl-N-nitrosourea (ENU), MLL-CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders. These represented the spectrum of therapy-induced acute myelomonocytic leukemia/chronic myelomonocytic leukemia/myelodysplastic/myeloproliferative disorder similar to that seen in humans possessing the t(11;16). This model of MLL-CBP therapy-related myeloproliferative disease demonstrates the selectivity of this MLL fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations.     

Case report of isochromosome 17q in acute myeloid leukemia with myelodysplasia-related changes after treatment with a hypomethylating agent

Isochromosome 17q is a relatively common karyotypic abnormality in medulloblastoma, gastric, bladder, and breast cancers. In myeloid disorders, it is observed during disease progression and evolution to acute myeloid leukemia in Philadelphia-positive chronic myeloid leukemia. It has been reported in rare cases of myelodysplastic syndrome, with an incidence of 0.4-1.57%. Two new agents have been approved for treatment of myelodysplastic syndrome/chronic myelomonocytic leukemia. These are the hypomethylating agents, 5-azacytidine and decitabine, recommended by consensus guidelines for high-risk myelodysplastic syndrome patients not eligible for hematopoietic stem cell transplantation. We present a case of chronic myelomonocytic leukemia with normal cytogenetics at diagnosis treated with decitabine (with good response); however, the patient evolved to acute myeloid leukemia with i(17q) shortly after suspending treatment. To the best of our knowledge, this is the first report of acute myeloid leukemia with myelodysplasia-related changes with i(17q) after the use of a hypomethylating agent.     

Myeloblastoma of the brain and spinal cord in a patient with acute myelomonocytic leukemia

A case of the myeloblastoma involving brain and spinal cord in a patient with acute myelomonocytic leukemia is reported. Numerous mitoses within the tumor provide an evidence for local cell proliferation in the neoplasm. Surgery combined with radiotherapy is suggested as the most efficient modality of the treatment.     

Acute myelomonocytic leukaemia with abnormal eosinophils and inversion of chromosome 16

We report a further case of a recently recognized variety of acute myelomonocytic leukaemia (M4 subtype) with bone marrow eosinophilia and inversion of chromosome 16. The eosinophils showed a distinctly abnormal morphology, cytochemical staining and ultrastructure.     

Studies on satellite nucleoli in human blastic cells of acute leukaemias.

Blastic cells of acute lymphoid, acute myeloid and acute myelomonocytic leukaemias were studied by means of indirect immunofluorencence to provide more information on the presence of satellite nucleoli in blood cells. According to results, satellite nucleoli were found in a small but constant number of blastic cells disregarding their type and type of acute leukaemia. Satellite nucleoli exhibited a positive immunoreaction for fibrillarin and protein B23 which are characteristic for main nucleolar components. These findings suggest that satellite nucleoli contain fibrillar centers as well as dense fibrillar and granular components or at least proteins characteristic for these nucleolar components. Similarly as in normal and pathological cells of completely different origin, in blastic cells of acute leukaemias the number of satellite nucleoli per cells ranged between 1 and 2.     

LEUKEMIA AFTER RADIOIODINE THERAPY FOR HYPERTHYROIDISM

In a group of 650 patients with hyperthyroidism treated with radioiodine between 1945 and 1961, two cases of leukemia occurred. In one patient the diagnosis of chronic lymphatic leukemia was made three years after the I(131) therapy. Acute or subacute myelomonocytic leukemia developed in the other patient after an interval of 14 years. However, no conclusions can be drawn regarding a possible causal relationship between such therapy and the subsequent occurrence of leukemia. With passage of time, an ever increasing number of cases of leukemia can be expected in such patients on the basis of natural occurrence alone.     

Nucleolar immunofluorescence in human hematological malignancies.

Rabbit antibodies to the nuclear Tris extract of HeLa cells which have been shown by the indirect immunofluorescence technique to localize in nucleoli of a variety of human malignant tumors but not in a number of nontumor tissues also produced bright fluorescence in nucleoli of tumor cells in several hematological malignancies. The tumors studied included Hodgkins malignant lymphoma, non-Hodgkins malignant lymphoma, acute myeloid and acute myelomonocytic leukemia, chronic lymphatic and chronic myeloid leukemia. In contrast, none of the corresponding normal cell lines in the bone marrow exhibited bright nucleolar fluorescence. In addition, neither the cells of patients with acute infectious mononucleosis nor lymphoid hyperplasia exhibited bright nucleolar fluorescence. These studies suggest that antibodies to HeLa cell nucleolar antigens may be useful in immunodiagnosis of human malignancies.     

On the presence of lysozyme in the Nuclei of Leukocytes.

The purified chromatin of leukocyte nuclei from two patients, one with chronic granulocytic and another with acute myelomonocytic leukemia, has been investigated for lysozyme activity. The chromatin contained 4.8% resp. 4% of the total amount of lysozyme found in the leukocytes. The function of lysozyme in the nucleus remains unclear.     

Myelosarcomatosis of the skin preceding leukemic generalization of acute myelomonocytic leukemia

A case report of a patient with myelosarcomatosis of the skin six months preceding leukemic generalization of acute myelomonocytic leukemia is presented. To the best of our knowledge this is the first case of a myelosarcoma with generalized skin involvement diagnosed before development of an overt myeloproliferative disease.     

Strategies for administering targeted therapeutic oligodeoxynucleotides.

Antisense or antigene DNA therapy of diseases that are due to aberrant gene expression is an exciting possibility. A variety of synthetic DNA derivatives has been applied in attempts to regulate the expression of many different genes, both in cell culture and in intact organisms (e.g. mice). Realistic design of human oligodeoxynucleotide-based therapeutic strategies requires many aspects of a candidate disease to be considered (including the disease prevalence, the number and nature of genes and mutations involved, and the tissues which must be targeted). For each DNA derivative intended for therapy, methods of targeting, modes of administration, pharmacokinetics, tissue distribution, toxicity, degradation and excretion must all be considered.     

Spontaneous remission of acute myeloid leukemia. A report of a case and brief review of the literature

A patient with acute myelomonocytic leukemia who experienced a spontaneous remission, is reported. He had precedent and concurrent bacterial infections as most of these cases described. Low peripheral WBC and myeloblasts, Auer-rod positive blasts, bone marrow eosinophilia with atypical eosinophils, and a partial deletion of chromosome 16 were favorable prognostic parameters. A brief review of the literature and possible explanations for the regulation of granulopoiesis are presented.