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Approximately 60%-80% of patients who achieve complete remission eventually relapse after conventional chemotherapy and have poor prognoses despite the recent advances of novel anticancer agents. Continuing development of more effective novel treatments for acute myeloid leukemia (AML) is necessary. We developed (R)-WAC-224 (R-WAC), which is an anticancer quinolone, targeting topoisomerase II. This study evaluated the anti-leukemia potential of R-WAC or racemic WAC-224 (WAC) in vitro and in vivo. R-WAC significantly inhibited the human AML cell line proliferation (MV4-11, HL60, and KG1a), which was comparable to daunorubicin and cytarabine, not affected by P-glycoprotein overexpression. WAC did neither increase serum troponin-T nor decrease the crypt numbers in the small intestine, indicating WAC was less toxic than doxorubicin. R-WAC monotherapy demonstrated prolonged survival in the AML mice model and inhibited tumor growth in the MV4-11 xenograft mice model. Moreover, the combination of R-WAC and cytarabine demonstrated more active anti-leukemia effects than daunorubicin and cytarabine. Finally, R-WAC inhibited the colony-forming abilities using primary AML cells. These results indicate that R-WAC is a promising therapeutic agent for AML., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

DDX41 mutation has been observed in myeloid malignancies including myelodysplastic syndromes and acute myeloid leukemia, but the underlying causative mechanisms of these diseases have not been fully elucidated. The DDX41 protein is an ATP-dependent RNA helicase with roles in RNA metabolism. We previously showed that DDX41 is involved in ribosome biogenesis by promoting the processing of newly transcribed pre-ribosomal RNA. To build on this finding, in this study, we leveraged ribosome profiling technology to investigate the involvement of DDX41 in translation. We found that DDX41 knockdown resulted in both translationally increased and decreased transcripts. Both gene set enrichment analysis and gene ontology analysis indicated that ribosome-associated genes were translationally promoted after DDX41 knockdown, in part because these transcripts had significantly shorter transcript length and higher transcriptional and translational levels. In addition, we found that transcripts with 5'-terminal oligopyrimidine motifs tended to be translationally upregulated when the DDX41 level was low. Our data suggest that a translationally regulated feedback mechanism involving DDX41 may exist for ribosome biogenesis., (© 2023. Japanese Society of Hematology.)

Erythroid sarcoma is a very rare subtype of myeloid sarcoma with undetermined biological features. Here, we present an infant with a multifocal erythroid sarcoma, diagnosed because the tumor cells were positive for glycophorin A. After acute myeloid leukemia-oriented chemotherapy and surgical resection followed by cord blood transplantation, he has successfully maintained complete remission without any late effects. Total transcriptome analysis of the tumor identified a novel fusion gene, RCC1-LCK, and high LCK expression levels, suggesting that LCK overexpression was involved in leukemogenesis in this case., (© 2022 Wiley Periodicals LLC.)

Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3' end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3' splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3)., (© 2022 by The American Society of Hematology.)

Revertant (somatic) mosaicism is a spontaneous correction of a causative mutation in patients with congenital diseases. A relatively frequent event, revertant mosaicism may bring favorable outcomes that ameliorate disorders, and is therefore called "natural gene therapy." However, it has been revealed recently that "overcorrection" of inherited bone marrow failure in patients with sterile alpha motif domain containing 9 (SAMD9)/9L syndromes by revertant mosaicism induces myelodysplastic syndrome (MDS) with monosomy 7 that occasionally proceeds to acute myelogenous leukemia (AML). In this review, we interpret very complex mechanisms underlying MDS/AML in patients with SAMD9/9L syndromes. This includes multiple myeloid tumor suppressors on the long arm of chromosome 7, all of which act in a haploinsufficient fashion, and a difference in sensitivity to interferon between cells carrying a mutation and revertants. Overcorrection of mutants by somatic mosaicism is likely a novel mechanism in carcinogenesis., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Loss-of-function mutations in ten-eleven translocation-2 (TET2) are recurrent events in acute myeloid leukemia (AML) as well as in preleukemic hematopoietic stem cells (HSCs) of age-related clonal hematopoiesis. TET3 mutations are infrequent in AML, but the level of TET3 expression in HSCs has been found to decline with age. We examined the impact of gradual decrease of TET function in AML development by generating mice with Tet deficiency at various degrees. Tet2f/f and Tet3f/f mice were crossed with mice expressing Mx1-Cre to generate Tet2f/wtTet3f/fMx-Cre+ (T2ΔT3), Tet2f/fTet3f/wtMx-Cre+ (ΔT2T3), and Tet2f/fTet3f/fMx-Cre+ (ΔT2ΔT3) mice. All ΔT2ΔT3 mice died of aggressive AML at a median survival of 10.7 weeks. By comparison, T2ΔT3 and ΔT2T3 mice developed AML at longer latencies, with a median survival of ∼27 weeks. Remarkably, all 9 T2ΔT3 and 8 ΔT2T3 mice with AML showed inactivation of the remaining nontargeted Tet2 or Tet3 allele, respectively, owing to exonic loss in either gene or stop-gain mutations in Tet3. Recurrent mutations other than Tet3 were not noted in any mice by whole-exome sequencing. Spontaneous inactivation of residual Tet2 or Tet3 alleles is a recurrent genetic event during the development of AML with Tet insufficiency., (© 2020 by The American Society of Hematology.)

ASXL1 plays key roles in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies, at least in part, via derepression of posterior HOXA loci. However, little is known about the identity of proteins that interact with ASXL1 and about the functions of ASXL1 in modulation of the active histone mark, such as H3K4 methylation. In this study, we demonstrate that ASXL1 is a part of a protein complex containing HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation. Disruption of this novel axis inhibited myeloid differentiation and H3K4 methylation as well as H2B glycosylation and impaired transcription of genes involved in myeloid differentiation, splicing, and ribosomal functions; this has implications for myelodysplastic syndrome (MDS) pathogenesis, as each of these processes are perturbed in the disease. This axis is responsible for tumor suppression in the myeloid compartment, as reactivation of OGT induced myeloid differentiation and reduced leukemogenecity both in vivo and in vitro. Our data also suggest that MLL5, a known HCFC1/OGT-interacting protein, is responsible for gene activation by the ASXL1-OGT axis. These data shed light on the novel roles of the ASXL1-OGT axis in H3K4 methylation and activation of transcription.

HLA-Flow is a flow cytometry-based method using anti-HLA antibodies against mismatched HLA alleles combined with the antibodies against antigens expressed on leukemic cells. It is a sensitive assay to determine minimal residual disease (MRD) after HLA mismatched hematopoietic stem cell transplantation (HSCT). In this study, we report the results of our HLA-Flow using six-color based multicolor fluorescence-activated cell sorting for HLA-mismatched HSCT. We performed HLA-Flow monitoring after HLA mismatched HSCT from July 2013 to July 2016 in nine patients (three with acute lymphoblastic leukemia, five with acute myeloid leukemia, and one with therapy-related acute myeloid leukemia) for MRD monitoring. We detected a relapse after HSCT in three of the nine patients, two of them at MRD levels. HLA-Flow is a sensitive, fast, and inexpensive method for the detection of MRD in patients with HLA-mismatched HSCT.

The DDX41 gene, encoding a DEAD-box type ATP-dependent RNA helicase, is rarely but reproducibly mutated in myeloid diseases. The acquired mutation in DDX41 is highly concentrated at c.G1574A (p.R525H) in the conserved motif VI located at the C-terminus of the helicase core domain where ATP interacts and is hydrolyzed. Therefore, it is likely that the p.R525H mutation perturbs ATPase activity in a dominant-negative manner. In this study, we screened for the DDX41 mutation of CD34-positive tumor cells based on mRNA sequencing and identified the p.R525H mutation in three cases among 23 patients. Intriguingly, these patients commonly exhibited acute myeloid leukemia (AML) with peripheral blood cytopenias and low blast counts, suggesting that the mutation inhibits the growth and differentiation of hematopoietic cells. Data from cord blood cells and leukemia cell lines suggest a role for DDX41 in preribosomal RNA processing, in which the expression of the p.R525H mutant causes a certain ribosomopathy phenotype in hematopoietic cells by suppressing MDM2-mediated RB degradation, thus triggering the inhibition of E2F activity. This study uncovered a pathogenic role of p.R525H DDX41 in the slow growth rate of tumor cells. Age-dependent epigenetic alterations or other somatic changes might collaborate with the mutation to cause AML., (Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

The recurrence of chromosomal abnormalities in a specific subtype of cancer strongly suggests that dysregulated gene expression in the corresponding region has a critical role in disease pathogenesis. -7/7q-, defined as the entire loss of chromosome 7 and partial deletion of its long arm, is among the most frequently observed chromosomal aberrations in myeloid-lineage hematopoietic malignancies such as myelodysplastic syndrome and acute myeloid leukemia, particularly in patients treated with cytotoxic agents and/or irradiation. Tremendous efforts have been made to clarify the molecular mechanisms underlying the disease development, and several possible candidate genes have been cloned. However, the study is still underway, and the entire nature of this syndrome is not completely understood. In this review, we focus on the attempts to identify commonly deleted regions in patients with -7/7q-; isolate the candidate genes responsible for disease development, cooperative genes and the factors affecting disease prognosis; and determine effective and potent therapeutic approaches. We also refer to the possibility that the accumulation of multiple gene haploinsufficiency, rather than the loss of a single tumor suppressor gene, may contribute to the development of diseases with large chromosomal deletions such as -7/7q-.

Mutations in ASXL1 are frequent in patients with myelodysplastic syndrome (MDS) and are associated with adverse survival, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) is not fully understood. Recently, it has been found that deletion of Asxl1 or expression of C-terminal-truncating ASXL1-MTs inhibit myeloid differentiation and induce MDS-like disease in mice. Here, we find that SET-binding protein 1 (SETBP1) mutations (SETBP1-MT) are enriched among ASXL1-mutated MDS patients and associated with increased incidence of leukemic transformation, as well as shorter survival, suggesting that SETBP1-MT play a critical role in leukemic transformation of MDS. We identify that SETBP1-MT inhibit ubiquitination and subsequent degradation of SETBP1, resulting in increased expression. Expression of SETBP1-MT, in turn, inhibited protein phosphatase 2A activity, leading to Akt activation and enhanced expression of posterior Hoxa genes in ASXL1-mutant cells. Biologically, SETBP1-MT augmented ASXL1-MT-induced differentiation block, inhibited apoptosis and enhanced myeloid colony output. SETBP1-MT collaborated with ASXL1-MT in inducing acute myeloid leukemia in vivo. The combination of ASXL1-MT and SETBP1-MT activated a stem cell signature and repressed the tumor growth factor-β signaling pathway, in contrast to the ASXL1-MT-induced MDS model. These data reveal that SETBP1-MT are critical drivers of ASXL1-mutated MDS and identify several deregulated pathways as potential therapeutic targets in high-risk MDS.

Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in ~\n10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML). Recent studies have shown that EZH2 mutations are often associated with RUNX1 mutations in MDS patients, although its pathological function remains to be addressed. Here we establish an MDS mouse model by transducing a RUNX1S291fs mutant into hematopoietic stem cells and subsequently deleting Ezh2. Ezh2 loss significantly promotes RUNX1S291fs-induced MDS. Despite their compromised proliferative capacity of RUNX1S291fs/Ezh2-null MDS cells, MDS bone marrow impairs normal hematopoietic cells via selectively activating inflammatory cytokine responses, thereby allowing propagation of MDS clones. In contrast, loss of Ezh2 prevents the transformation of AML via PRC1-mediated repression of Hoxa9. These findings provide a comprehensive picture of how Ezh2 loss collaborates with RUNX1 mutants in the pathogenesis of MDS in both cell autonomous and non-autonomous manners.

Radiation induced acute myeloid leukemia (AML) was recognized a century ago, soon after mankind found radiation. Atomic bomb survivors developed de novo AML with relatively short latency with very high frequency. By contrast, excess occurrence of myelodysplastic syndrome (MDS) as well as solid tumors was found decades late. This difference may be due to etiology that many de novo AML patients harbor chimeric leukemogenic genes caused by chromosomal translocations, while MDS patients rarely carry chimeras. In addition, epigenetic change would play important roles. Therapy related leukemia is mainly caused by topoisomerase II inhibitors that cause de novo AML with an 11q23 translocation or by alkyrating agents that induce MDS/AML with an AML1 point mutation and monosomy 7.

Myelodysplastic syndrome (MDS) is a hematopoietic stem-cell disorder characterized by trilineage dysplasia and susceptibility to acute myelogenous leukemia (AML). Analysis of molecular basis of MDS has been hampered by the heterogeneity of the disease. Recently, mutations of the transcription factor AML1/RUNX1 have been identified in 15% to 40% of MDS-refractory anemia with excess of blasts (RAEB) and MDS/AML. We performed mouse bone marrow transplantation (BMT) using bone marrow cells transduced with the AML1 mutants. Most mice developed MDS and MDS/AML-like symptoms within 4 to 13 months after BMT. Interestingly, among integration sites identified, Evi1 seemed to collaborate with an AML1 mutant harboring a point mutation in the Runt homology domain (D171N) to induce MDS/AML with an identical phenotype characterized by marked hepatosplenomegaly, myeloid dysplasia, leukocytosis, and biphenotypic surface markers. Collaboration between AML1-D171N and Evi1 was confirmed by a BMT model where coexpression of AML1-D171N and Evi1 induced acute leukemia of the same phenotype with much shorter latencies. On the other hand, a C-terminal truncated AML1 mutant (S291fsX300) induced pancytopenia with erythroid dysplasia in transplanted mice, followed by progression to MDS-RAEB or MDS/AML. Thus, we have developed a useful mouse model of MDS/AML that should help in the understanding of the molecular basis of MDS and the progression of MDS to overt leukemia.

AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML). Although AML1 mutations are suspected to play a pivotal role in the development of MDS/AML, acquisition of additional genetic alterations is also necessary. We analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with -7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of -5/5q- and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)-RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wild-type MDS/AML patients (38% versus 6.3%, P < 0.0001). Conversely, p53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced extracellular signal-regulated kinase activation following stem cell factor stimulation. Our results suggest that MDS/AML arising from AML1/RUNX1 mutations has a significant association with -7/7q- alteration, and frequently involves RTK-RAS signaling pathway activation.

A NUP98 gene translocation occurring with a del(6p23) and an add(11)(p15) was determined in a 61-year-old patient with therapy-related atypical chronic myelocytic leukemia after complete remission from acute promyelocytic leukemia that eventually underwent clonal evolution and transformed to CD56-positive acute myelocytic leukemia (French-American-British classification M0). Precise chromosome analysis by G-banding, spectral karyotyping analysis, and dual-color fluorescence in situ hybridization showed this abnormality as 46,XY,del(6)(p23),add(p15). ish del(6)(NUP98-,D6Z1+),der(7)(NUP98+,D7Z1+),der(11)(NUP98+,D11Z1). A split signal of NUP98 was observed in 68.4% of the 117 cells analyzed, which clearly indicated that the NUP98 partially translocated to chromosome 7. However, the potential fusion partner of the NUP98 was not HOX family or DEK. The fusion gene has not been found by a differential display method. The significance of simultaneously combined del(6)(p23), which also has been reported with secondary leukemogenesis, has not been elucidated. Additional karyotype abnormalities evolved increasingly, and leukocytosis with blasts with more complex karyotypic abnormalities appeared 5 months later. Careful and continuous analysis of karyotype change clarified the process of the clonal evolution after NUP98 translocation. Further investigation of molecular characterization of this NUP98 translocation and interaction with 6p23 abnormalities might be worthwhile for understanding leukemogenesis.

A 62-year-old man diagnosed with acute myelogenous leukemia which had developed from myelodysplastic syndrome received cytarabine and idarubicine as an induction therapy. The patient developed pneumonia and bacterial sepsis during profound neutropenia. Fever and sepsis improved by using many anti-bacterials and anti-fungals but he became febrile again and complained of severe lumbar pain. 67Ga scintigram showed abnormal uptake in the lumbar vertebra and left sternoclavicular joint, suggesting a diagnosis of discitis and osteomyelitis in the lumbar vertebra and sternoclavicular arthritis. We biopsied the site several times but culture of the biopsy specimen could not isolate any pathogens, and high fever persisted for about 10 months despite administration of various anti-bacterials and anti-fungals. Finally we inserted a catheter into the abscess at the iliopsoas muscle and Scedosporium apiospermum was isolated in the bloody pus obtained from the catheter. Itraconazole and amphotericin B were restarted, and the high fever and lumbar pain improved rapidly. The findings of S. apiospermum infection in this patient emphasizes the importance of being aware of this pathogen in patients with hematologic malignancy during the neutropenic phase.

A myeloid leukemia cell line designated Kasumi-6 was established from the bone marrow cells of an individual with acute myeloid leukemia, subtype M2. Both the original leukemic cells and the Kasumi-6 cell line harbor a hemizygous point mutation in the gene encoding the CCAAT/enhancer binding protein alpha (C/EBPalpha), a critical myeloid transcriptional factor. The C to G transition at nucleotide 1063 of the C/EBPalpha gene results in amino acid transition R305P in the fork or hinge region between the DNA-binding basic region and the leucine zipper dimerization domain of the C/EBPalpha protein. The Kasumi-6 cells expressed both the p42 and p30 isoforms of the C/EBPalpha protein endogenously, but electrophoretic mobility shift assays demonstrated an absence of C/EBPalpha binding to its respective site. Exogenous expression of the mutant form of C/EBPalpha demonstrated that it was unable to bind DNA and activate transcription from a G-CSF receptor-luciferase reporter construct. Furthermore, coexpression of the wild-type and mutant forms revealed that the mutant form repressed reporter gene activation by the wild type in a dose-responsive manner. This was concomitant with a dose-responsive decrease in wild-type protein binding to the G-CSF receptor C/EBP site. The data suggest that the R305P alteration confers a dominant-negative property on the mutant C/EBPalpha protein whereby the mutant polypeptide heterodimerizes with the wild-type polypeptide and prevents it from binding to DNA, thus blocking transcriptional activation. The Kasumi-6 cell line can serve as a model to study the cellular and molecular biology of the non-t(8;21) M2 type of myeloid leukemia and can elucidate the role of mutated C/EBPalpha in leukemogenesis., (Copyright 2003 Wiley-Liss, Inc.)

We report a patient with myelodysplastic syndrome (MDS) overt leukemia who developed an acute myeloid leukemia (AML) in donor cells shortly after bone marrow transplantation (BMT) from his HLA-matched sibling. Molecular analysis using microsatellite repeats by polymerase chain reaction proved the new leukemia to be of donor cell origin. The patient received chemotherapy with idarubicin and ara-C, but he died due to mucormycosis.

Thrombopoietin (TPO) is a ligand for c-mpl that promotes both proliferation and differentiation of megakaryocytes in vivo and in vitro. We investigated the expression of c-mpl transcripts and the effects of recombinant human TPO (rhTPO) on the proliferation and differentiation of human leukemic cell lines or fresh samples obtained from 32 patients with transient abnormal myelopoiesis (TAM) or acute myeloblastic leukemia (AML). Cells were cultured with TPO alone or combined with rh interleukin-3 (IL-3) or stem cell factor (SCF). Expression of c-mpl was verified in 6 of 13 cases tested. All but one of the cases that showed c-mpl expression responded to TPO. Blasts from all cases of TAM or French-American-British (FAB) subtype M7 showed growth responses to TPO with higher sensitivity than cells of other FAB subtypes and these responses were increased by addition of rhIL-3 or rhSCF in some cases. Responses of cells of other FAB subtypes varied. In addition, increased expression of platelet-specific surface antigens on MO7E cells after incubation with rhTPO was observed. These data suggest that TPO may be involved in the abnormal proliferation and differentiation of human leukemic cells, especially of M7 and TAM cells, considered to be of megakaryocytic lineage.

Three cases of secondary acute myeloid leukemia (AML) that developed after long term treatment with oral etoposide were reported. Case 1 was a 72-year-old male in whom small cell lung cancer was diagnosed in January 1987. He developed AML (M4) in February 1993 after long-term treatment with oral etoposide (total dose 14,650 mg) t(9; 11) (p21; q23) with rearrangement of MLL genes was recognized. Case 2 was a 68-year-old female non-Hodgkin's lymphoma (NHL) was diagnosed in February 1989. AML (M4Eo) with inv(16) (p13q22) developed in March 1994 after long-term treatment with oral etoposide (total dose 5,100 mg). Case 3 was a 39-year-old male in whom NHL was diagnosed in January 1991. He developed AML(M2) with t(11; 19) (q23; p13) in May 1994 after long-term treatment with oral etoposide (total dose 20,450 mg). These three cases suggest that long-term treatment with oral etoposide may be associated with a risk of developing a secondary AML in patient with malignancies.

A 77-year-old female with left hemiplegia caused by cerebral infarction and with mild senile dementia was admitted for further examination of hematological abnormalities. She was diagnosed as acute myelogenous leukemia (AML-M5a) according to French-American-British classification. Since intensive combination chemotherapy seemed difficult, she was treated with oral administration of cytarabine ocfosfate (200 mg/day, for 14 days), a cytidine deaminase-resistant derivative of Ara-C, resulting in complete remission. Major side effects were nausea, vomiting and appetite loss, but their incidences were reduced tolerably when cytarabine ocfosfate was given just before sleeping. Cytarabine ocfosfate might be useful to treat AML in elderly patients having certain complications such as cerebrovascular disease.

Two patients with acute myeloblastic leukemia are described who developed fungemia due to Trichosporon cutaneum. Fungemia occurred at the leukocyte nadir following the administration of anti-cancer chemotherapy. One patient was cured but the other died. Both patients received prednisolone continuously and had central venous catheters in place for parenteral hyperalimentation. T. cutaneum isolates were resistant to 5-fluorocytosine and moderately susceptible to fluconazole. One case was complicated by endophthalmitis due to T. cutaneum; this is the second report of such a complication in the world. We investigated the serum levels of beta-D-glucan, D-arabinitol, and Candida antigen (CAND-TEC); beta-D-glucan was elevated in both cases, which suggests that simultaneous measurements of these laboratory values are useful for the diagnosis and possibly for the evaluation of therapy for this fungal infection.

Because recombinant human granulocyte colony-stimulating factor (G-CSF) has been reported to increase the sensitivity of acute myelogenous leukemia (AML) blast cells to cytosine arabinoside (Ara-C) in vitro, we treated a patient with refractory AML with an Ara-C-based regimen in combination with G-CSF (G-CSF/Ara-C therapy). G-CSF (50 micrograms/m2/day, subcutaneous injection) was administered simultaneously with a continuous intravenous infusion of Ara-C (70 mg/m2/day). Complete remission was achieved, however, severe neutropenia, documented infection, stomatitis, and diarrhea were observed. In vitro studies using 3H-thymidine uptake and dual parameter flow-cytometric analysis of DNA and proliferating cell nuclear antigen showed that leukemic blast cells in S phase were increased after incubation with G-CSF. G-CSF also enhanced expression of the transferrin receptor (CD71) on blast cells in vitro. These observations suggest that G-CSF/Ara-C therapy may be useful in the treatment of high-risk AML.

A 25-year-old woman was diagnosed as acute myeloblastic leukemia (M1 in FAB classification) in May 1983, and treated with DCMP regimen, which led to the complete remission. Intensification therapies and maintenance therapy with OK-432 were continued until August 1988, and 10 months later she conceived. She delivered a healthy 2,680 g male baby at 36th week of pregnancy by Cesarean section because of abruptio placentae. This case suggests that normal pregnancy is possible in patients with acute leukemia who received anti-cancer drugs.

A 7-year-old girl with an acute leukemia was reported whose blasts showed conversion from a T-lymphoid to a myeloid phenotype. At the onset of the disease, the blasts were negative for peroxidase and displayed FAB L1 morphology. Surface marker analysis revealed only CD7 antigen. Although complete remission was achieved, an extramedullary relapse was identified as having a several subcutaneous tumors 15 months later. Tumor cells showed the same marker expression as that of the blasts at the onset. After short term culture without an addition of any differentiation stimulators, the blast cells expressed CD2, CD3, CD4, CD8, and CD25 antigens. The karyotype was 46, XX, t(12; 21) (p11; q22). The intensive chemotherapy and radiation therapy were carried out, however, a hematological relapse occurred 12 months later. At this time, the blasts were strongly positive for peroxidase and expressed HLA-DR and CD33 antigens with disappearance of the CD7 antigen. Chromosome analysis revealed the additional abnormalities (del (7) (p15), -17, +der (17) t (17;?) (p13;?].