[Haploidentical stem cell transplantation for acute myeloid leukemia associated with adult-onset Shwachman-Diamond syndrome].

A 21-year-old man presented with bone marrow failure, short stature, fatty degeneration of the pancreas on CT images, and Shwachman-Bodian-Diamond syndrome (SBDS) gene abnormalities (exon 2: c.258+2T>C and deletion of exon 3). Thus, the patient was diagnosed with Shwachman-Diamond syndrome (SDS). In the clinical course, the patient developed acute myeloid leukemia (AML). Hematopoietic stem cell transplantation from the human-leukocytic-antigen-haploidentical father of the patient was performed. The patient was conditioned with 150 mg/m2 fludarabine, 6.4 mg/kg busulfan, and 4 Gy total body irradiation. Graft-versus-host disease prophylaxis included tacrolimus, micophenolate mofetil, and posttransplant cyclophosphamide. Although the patient achieved a complete remission on day 21, AML relapsed on day 434 after the transplantation. He died of sepsis. The prognosis of patients with SDS and AML is poor. Adult-onset cases must be recognized, and transplantation should be performed during bone marrow failure.

[Leukemic cell kinetics of APL with a novel complex variant t (12;17;15)(p13;q21;q22)].

A 69-year-old woman with leukocytopenia and thrombocytopenia was referred to our hospital. Her bone marrow comprised 70.5% abnormal promyelocytes that were positive for myeloperoxidase/CD33/CD117 and CD13 (dim) and negative for CD2/CD34/CD56 and HLA-DR. Chromosome analysis of the bone marrow showed t (12;17;15) (p13;q21;q22), and fluorescence in situ hybridization revealed the PML-RARA fusion signal only on the derivative chromosome 15. The patient was diagnosed with acute promyelocytic leukemia (APL) with PML-RARA and was treated using all-trans retinoic acid (ATRA). In peripheral blood (PB), PML-RARA-positive polymorphonuclear cells (PMNs) appeared on the second week and became negative on the sixth week after treatment, whereas PML-RARA-negative PMNs started to increase in number on the sixth week. Molecular remission was confirmed on the 10th week. Quantitative evaluation of the differentiated leukemic cells of APL and recovered cells from normal hematopoiesis in PB can provide useful information for a safer induction therapy. No significant difference was noted in the kinetics of the leukemic cells under ATRA treatment as well as in the clinical features between our patient without RARA-PML and those with t (15;17), which is a cytogenetic evidence for the critical role of PML-RARA in the pathogenesis of APL.

Light-chain plasma cell myeloma caused by 14q32/IGH translocation and loss of the other allele.

Light-chain plasma cell myeloma (LC-PCM) is a PCM subtype in which only immunoglobulin light-chain is secreted. However, the absence of immunoglobulin heavy-chain (IGH) production in this condition has not been fully elucidated. To address this issue, we retrospectively analyzed patients at our center with LC-PCM and found a group who had only split signals of IGH gene derived from 14q32/IGH translocations by fluorescence in situ hybridization (FISH). Six patients were identified with only split signals of the IGH gene derived from 14q32/IGH translocations. Five of these patients were newly diagnosed, while one had IgG-λ PCM at presentation, which transformed to λ LC-PCM after treatment. The translocation partners were identified in four patients: two cases of (11;14)(q13;q32) and two cases of (4;14)(p16;q32). The development of LC-PCM appears to be explained by the application of allelic exclusion in these patients, such that 14q32/IGH translocation in one allele contributes to the pathogenesis of PCM and the subsequent loss of the other allele is responsible for the loss of IGH production. These findings suggest that a FISH pattern of IGH with "split and loss" may constitute a unique subgroup of LC-PCM.

Efficacy of Recombinant Human Soluble Thrombomodulin in Treating Disseminated Intravascular Coagulation Complicating Allogeneic Hematopoietic Stem Cell Transplantation.

The prognosis for patients who experience hemostatic complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poor. However, no report has investigated disseminated intravascular coagulation (DIC) caused by the complications of allo-HSCT without infection. Recombinant human soluble thrombomodulin (rhTM) was used to treat 12 episodes of DIC (n = 10; group 1) caused by allo-HSCT complications such as acute graft-versus-host disease (aGVHD) or thrombotic microangiopathy (TMA), and the clinical outcomes were compared with those of historical controls (n = 9; group 2) treated for DIC without rhTM. In group 1, the mean DIC score was significantly improved after using rhTM. Fibrinogen degeneration product (FDP), C-reactive protein (CRP), and the inflammatory cytokine high-mobility group box 1 (HMGB1) were also significantly decreased. Serial changes from the baseline values of platelet counts and levels of FDP were significantly better in group 1 than in group 2. The recovery rate from DIC was significantly higher in group 1 than in group 2. These findings suggest that rhTM is effective against both DIC and systemic inflammatory complications after allo-HSCT.

Correction to: Cell dynamics during differentiation therapy with all-trans retinoic acid in acute promyelocytic leukemia.

In the original publication of the article, Table 2 was published incorrectly. The column names were swapped under the column heading "Prom (%)". The correct column names are PB and BM.

Cell dynamics during differentiation therapy with all-trans retinoic acid in acute promyelocytic leukemia.

The introduction of all-trans retinoic acid (ATRA) has made acute promyelocytic leukemia (APL) a curable disease; however, early death prior to the completion of treatment remains a problem. In quantitative evaluation of response to ATRA treatment, lymphocytes must be excluded as they do not originally have t(15;17). We categorized peripheral blood leukocytes by nuclear morphology into polymorphonuclear cells (PMNs) comprising segmented granulocytes, and non-polymorphonuclear cells (NPMs) which includes lymphocytes, monocytes, band cells, and immature myeloid cells. We consecutively evaluated the ratio of t(15;17)-positive cells using fluorescence in situ hybridization in eight newly diagnosed patients with APL. We confirmed the differentiation of APL cells until cytogenetic complete remission; the association of a decrease of t(15;17)-positive NPMs and an increase of t(15;17)-positive PMNs was followed by a decrease of t(15;17)-positive PMNs. The kinetic pattern of t(15;17)-positive NPMs and PMNs was consistent in most patients, irrespective of leukocyte counts at diagnosis, additional chromosomal changes, and ATRA with or without chemotherapies. Kinetic analysis enables us to evaluate treatment response and the recovery of normal hematopoiesis in individuals.

[MALT lymphoma with t (X;14) (p11.2;q32) developing during the course of cutaneous leukocytoclastic angitis].

A 73-year-old man with left parotid gland swelling over 2 months was referred to our hospital in March 201X. Purpura on the lower legs had been recurrent for >20 years. Biopsy of the parotid gland demonstrated diffuse infiltration of abnormal lymphocytes that were negative for CD10 and positive for CD19, CD20, and κ-chain. The Ki-67 positivity was <10%; lymphoepithelial lesions were observed. The patient was diagnosed with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Chromosome analysis revealed t (X;14) (p11.2;q32), and fluorescence in situ hybridization (FISH) of metaphase spreads showed three signals of the immunoglobulin heavy chain (IGH) gene on the derivative chromosomes X and 14, besides the normal chromosome 14. CT findings of parotid glands were suggestive of Sjogren syndrome, and biopsy of the purpura on the leg demonstrated leukocytoclastic vasculitis. In the literature, only seven patients with lymphoma and t (X;14) translocation have been reported. Of these, five patients had MALT lymphoma, one had nodal marginal zone lymphoma, and one had diffuse large B-cell lymphoma. In all patients, lymphoma evolved from previous autoimmune diseases. It is suggested that MALT lymphoma with the t (X;14) translocation forms a new entity of lymphoma.

Combined treatment with benzo[a]pyrene and 1α,25-dihydroxyvitamin D3 induces expression of plasminogen activator inhibitor 1 in monocyte/macrophage-derived cells.

Benzo[a]pyrene (BaP) is an environmental pollutant found in cigarette smoke and is implicated as a causative agent of tobacco-related diseases, such as arteriosclerosis. In contrast, vitamin D signaling, which is principally mediated by conversion of vitamin D to the active form, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], decreases cardiovascular disease risk. However, combined treatment with BaP and 1,25(OH)2D3 enhances BaP toxicity, including BaP-DNA adduct formation. We further investigated the cross-talk between BaP and 1,25(OH)2D3 signaling pathways, and found that combined treatment with these compounds induces mRNA and protein expression of plasminogen activator inhibitor 1 (PAI-1) in monocyte/macrophage-derived THP-1 and U937 cells. Protein synthesis inhibitor treatment did not inhibit induction of the PAI-1 gene (SERPINE1) in these cells. BaP plus 1,25(OH)2D3 induced differentiation markers, inhibited cellular proliferation, and induced apoptosis and oxidative stress in these cells. Reactive oxygen species scavenger treatment suppressed apoptosis but not SERPINE1 induction in cells treated with BaP plus 1,25(OH)2D3. Thus, combined treatment with BaP and 1,25(OH)2D3 induced SERPINE1 mRNA expression in these cells through a mechanism that does not require de novo protein synthesis or reactive oxygen species production. These findings suggest that induction of the proinflammatory factor PAI-1 plays a role in BaP toxicity. Interestingly, PAI-1 knockdown decreased expression of the cell surface antigen CD14, a monocytic differentiation marker, in THP-1 cells treated with BaP plus 1,25(OH)2D3. PAI-1 induction may also be related to a function of monocytes/macrophages in response to xenobiotic and vitamin D signaling.

Acute myeloid leukemia with t (3;8) (q26.2;q24), a simple variant of 3q26.2/EVI1 translocation.

A 70-year-old man with pancytopenia was referred to our hospital. His bone marrow comprised 75.4% leukemic blast cells and increased micromegakaryocytes. The leukemic cells were positive for myeloperoxidase and expressed CD2, CD13, CD33, CD34, CD56, CD117, HLA-DR, and MYC. Chromosomal analysis revealed 45,XY,t (3;8) (q26.2;q24),-7[6]/46,XY[14]. Fluorescence in situ hybridization revealed the rearrangement of the ecotropic viral integration site 1 (EVI1) gene. Thus, the patient was diagnosed as having acute myeloid leukemia (AML) with maturation, according to the WHO classification; he achieved complete cytogenetic remission after two courses of combination chemotherapy using anthracyclines and cytarabine. The t (3;8) translocation is a rare simple variant of the 3q26.2/EVI1 translocation, which is an adverse prognostic factor of AML. Clarifying the clinical features of leukemia in patients with simple variant translocations facilitates the development of therapies.

T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presented as T-Lymphoid Hyperplasia Involving the Central Nervous System.

We herein report a case of T-cell/histiocyte-rich large B-cell lymphoma which initially presented as a self-limiting T-lymphoproliferative disorder involving multiple extranodal and extrapulmonary organs, such as the salivary gland, the liver, and the central nervous system. Repeated biopsies only revealed polyclonal T-lymphocytosis without the presence of atypical B-cells. Angiocentric cellular infiltration was absent, thus ruling out lymphomatoid granulomatosis. A recurrence in the lymphatic system finally revealed a small population of pathognomonic atypical B-cells, which led to the diagnosis. The clinical dilemma in the diagnosis and management of this indeterminate condition points to limitations in the current nosology.

Acute myeloid leukemia with t(3;21)(q13;q22), a novel simple variant of the 21q22/RUNX1 translocation.

A 69-year-old man diagnosed with leukocytosis was referred to our hospital in July 201X. The patient was diagnosed as having a myelodysplastic/myeloproliferative neoplasm. However, he presented with leukemia 2 months later. Chromosomal analysis of a bone marrow sample documented that this patient had a normal karyotype. The patient was successfully treated with idarubicin and cytarabine, and he underwent three courses of consolidation therapy. However, he suffered a relapse in May of the following year. A cytogenetic analysis revealed the presence of a t (3;21) (q13;q22) translocation, and fluorescence in situ hybridization of metaphase spreads detected three signals corresponding to the runt related transcription factor 1 (RUNX1) on the derivative chromosomes 3 and 21, besides the normal chromosome 21. Chromosomal translocations in leukemia often involve genes encoding transcription factors, and the RUNX1 is a common target for such translocations. To the best of our knowledge, this is a novel variant of the RUNX1 translocation. Identifying genes associated with translocations in leukemia contributes to novel insights into the mechanisms of disease progression and chemotherapy resistance and also facilitates the development of molecularly targeted therapies.

PAX5-positive plasma cell myeloma with t(9;14;11)(p13;q32;q13), a novel complex variant translocation of t(11;14)(q13;q32) and t(9;14)(p13;q32).

We describe herein the case of a 64-year-old man with a diagnosis of plasma cell myeloma (PCM). A chromosome analysis based on G-banding and spectral karyotyping revealed the following complex karyotype: 46,XY,del(3)(p?), t(4;15)(q31;q24),t(9;14;11)(p13;q32;q13),add(15)(q24),add(18)(q21). Fluorescence in situ hybridization (FISH) detected one signal each for the immunoglobulin heavy chain (IGH) and cyclin D1 (CCND1) genes, and three fusion signals of IGH and CCND1. FISH analysis of metaphase spreads revealed fusion signals on the derivative chromosomes 9, 11, and 14. Immunohistochemical analysis identified abnormal expression of CCND1 and PAX5. PAX5-positive PCM is rare because the down-regulation of PAX5 is essential for the terminal differentiation of B cells into plasma cells. To the best of our knowledge, this is the first reported case of a novel complex variant translocation of t(11;14)(q13;q32) and t(9;14)(p13;q32).

Cytogenetic Study and Analysis of Protein Expression in Plasma Cell Myeloma with t(11;14)(q13;q32): Absence of BCL6 and SOX11, and Infrequent Expression of CD20 and PAX5.

The t(11;14)(q13;q32) translocation is the most common chromosomal translocation in plasma cell myeloma (PCM), but the cytogenetic and immunophenotypic features of PCM with t(11;14)(q13;q32) remain to be fully elucidated. To address the issue, we retrospectively analyzed 21 newly diagnosed PCM patients with the t(11;14)(q13;q32) translocation in our institute. CD20 is a B-cell-specific transmembrane protein that is the topic of much focus as a potential target in immunotherapy. We observed a low incidence of CD20 expression (2 of 21 patients, 11%), although the expression of CD20 was previously reported to be associated with t(11;14)(q13;q32). PAX5 is an essential transcriptional factor involved in B-cell development and commitment, and is down-regulated upon plasma cell differentiation. We observed one patient (6%) with expression of PAX5. The expression of CD19, CD56, and CD138 was detected in one (0.7%), nine (60%), and 13 patients (87%), respectively. Cyclin D1, CD38, and BCL2 were detected in all patients; on the other hand, neither BCL6 nor SOX11 was detected in any of the evaluated patients. Abnormalities of chromosome 13 were detected in six patients (38%), but deletion of TP53 was not observed in any of the evaluated patients. Our results suggest the absence of BCL6 and SOX11 expression, and infrequent expression of CD20, PAX5, and CD56 in PCM with t(11;14)(q13;q32), in contrast to the findings of earlier reports.

Vitamin D receptor activation enhances benzo[a]pyrene metabolism via CYP1A1 expression in macrophages.

Benzo[a]pyrene (BaP) activates the aryl hydrocarbon (AHR) and induces the expression of genes involved in xenobiotic metabolism, including CYP1A1. CYP1A1 is involved not only in BaP detoxification but also in metabolic activation, which results in DNA adduct formation. Vitamin D receptor (VDR) belongs to the NR1I subfamily of the nuclear receptor superfamily, which also regulates expression of xenobiotic metabolism genes. We investigated the cross-talk between AHR and VDR signaling pathways and found that 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a potent physiological VDR agonist, enhanced BaP-induced transcription of CYP1A1 in human monocytic U937 cells and THP-1 cells, breast cancer cells, and kidney epithelium-derived cells. 1,25(OH)(2)D(3) alone did not induce CYP1A1, and 1,25(OH)(2)D(3) plus BaP did not increase CYP1A2 or CYP1B1 mRNA expression in U937 cells. The combination of 1,25(OH)(2)D(3) and BaP increased CYP1A1 protein levels, BaP hydroxylation activity, and BaP-DNA adduct formation in U937 cells and THP-1 cells more effectively than BaP alone. The combined effect of 1,25(OH)(2)D(3) and BaP on CYP1A1 mRNA expression in U937 cells and/or THP-1 cells was inhibited by VDR knockdown, VDR antagonists, and α-naphthoflavone, an AHR antagonist. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays showed that VDR directly bound to an everted repeat (ER) 8 motif in the human CYP1A1 promoter. Thus, CYP1A1 is a novel VDR target gene involved in xenobiotic metabolism. Induction of CYP1A1 by the activation of VDR and AHR may contribute to BaP-mediated toxicity and the physiological function of this enzyme.

Increased nuclear expression and transactivation of vitamin D receptor by the cardiotonic steroid bufalin in human myeloid leukemia cells.

The active form of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], is a potent ligand for the nuclear receptor vitamin D receptor (VDR) and induces myeloid leukemia cell differentiation. The cardiotonic steroid bufalin enhances vitamin D-induced differentiation of leukemia cells and VDR transactivation activity. In this study, we examined the combined effects of 1,25(OH)(2)D(3) and bufalin on differentiation and VDR target gene expression in human leukemia cells. Bufalin in combination with 1,25(OH)(2)D(3) enhanced the expression of VDR target genes, such as CYP24A1 and cathelicidin antimicrobial peptide, and effectively induced differentiation phenotypes. An inhibitor of the Erk mitogen-activated protein (MAP) kinase pathway partially inhibited bufalin induction of VDR target gene expression. 1,25(OH)(2)D(3) treatment induced transient nuclear expression of VDR in HL60 cells. Interestingly, bufalin enhanced 1,25(OH)(2)D(3)-induced nuclear VDR expression. The MAP kinase pathway inhibitor increased nuclear VDR expression induced by 1,25(OH)(2)D(3) and did not change that by 1,25(OH)(2)D(3) plus bufalin. A proteasome inhibitor also enhanced 1,25(OH)(2)D(3)-induced CYP24A1 expression and nuclear VDR expression. Bufalin-induced nuclear VDR expression was associated with histone acetylation and VDR recruitment to the CYP24A1 promoter in HL60 cells. Thus, the Na(+),K(+)-ATPase inhibitor bufalin modulates VDR function through several mechanisms, including Erk MAP kinase activation and increased nuclear VDR expression.

The aryl hydrocarbon receptor activator benzo[a]pyrene enhances vitamin D3 catabolism in macrophages.

Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon produced by cigarette combustion, is implicated as a causative agent in smoking-related cancer and atherosclerosis. 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], a potent ligand for the nuclear receptor vitamin D receptor (VDR), has been shown to decrease the risk of osteoporosis, some types of cancer and cardiovascular disease, suggesting an opposing effect of vitamin D3 to cigarette smoking. In this study, we investigated the effects of BaP on the vitamin D3 signaling pathway. BaP effectively enhanced the 1,25(OH)2D3-dependent induction of cytochrome P450 24A1 (CYP24A1) in human monocyte/macrophage-derived THP-1 cells and breast cancer MCF-7 cells. BaP combination was less or not effective on mRNA expression of CD14, arachidonate 5-lipoxygenase, and cathelicidin antimicrobial peptide in THP-1 cells. BaP also increased the expression of CYP24A1 induced by a non-vitamin D VDR ligand, lithocholic acid acetate. Another aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, enhanced CYP24A1 expression by 1,25(OH)2D3 in THP-1 cells. Treatment of cells with an AhR antagonist and a protein synthesis inhibitor inhibited the enhancing effect of BaP on CYP24A1 induction, indicating that the effects of BaP are mediated by AhR activation and de novo protein synthesis. BaP pretreatment increased 1,25(OH)2D3-dependent recruitment of VDR and retinoid X receptor to the CYP24A1 promoter. Analysis of 1,25(OH)2D3 metabolism showed that BaP enhanced the hydroxylation of 1,25(OH)2D3 by CYP24A1 in THP-1 cells. Thus, AhR activation by BaP stimulates vitamin D3 catabolism. Modulation of vitamin D signaling by AhR may represent a mechanism underlying cigarette smoking-related diseases.

Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia.

1alpha,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a vitamin D receptor (VDR) ligand, regulates calcium homeostasis and also exhibits noncalcemic actions on immunity and cell differentiation. In addition to disorders of bone and calcium metabolism, VDR ligands are potential therapeutic agents in the treatment of immune disorders, microbial infections, and malignancies. Hypercalcemia, the major adverse effect of vitamin D(3) derivatives, limits their clinical application. The secondary bile acid lithocholic acid (LCA) is an additional physiological ligand for VDR, and its synthetic derivative, LCA acetate, is a potent VDR agonist. In this study, we found that an additional derivative, LCA propionate, is a more selective VDR activator than LCA acetate. LCA acetate and LCA propionate induced the expression of the calcium channel transient receptor potential vanilloid type 6 (TRPV6) as effectively as that of 1alpha,25-dihydroxyvitamin D(3) 24-hydroxylase (CYP24A1), whereas 1,25(OH)(2)D(3) was more effective on TRPV6 than on CYP24A1 in intestinal cells. In vivo experiments showed that LCA acetate and LCA propionate effectively induced tissue VDR activation without causing hypercalcemia. These bile acid derivatives have the ability to function as selective VDR modulators.

Vitamin D3 derivatives with adamantane or lactone ring side chains are cell type-selective vitamin D receptor modulators.

The vitamin D receptor (VDR) mediates the biological actions of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the active form of vitamin D, which regulates calcium homeostasis, immunity, cellular differentiation, and other physiological processes. We investigated the effects of three 1,25(OH)(2)D(3) derivatives on VDR function. AD47 has an adamantane ring and LAC67a and LAC67b have lactone ring substituents at the side chain position. These vitamin D derivatives bind to VDR but do not stabilize an active cofactor conformation. In a VDR transfection assay, AD47 and LAC67b act as partial agonists and all three compounds inhibit VDR activation by 1,25(OH)(2)D(3). The derivatives enhanced the heterodimerization of VDR with the retinoid X receptor, an effect unrelated to agonist/antagonist activity. AD47 and LAC67b weakly induced recruitment of the SRC-1 cofactor to VDR, and all three derivatives inhibited the recruitment of p160 family cofactors to VDR induced by 1,25(OH)(2)D(3). It is noteworthy that AD47 induced DRIP205 recruitment as effectively as 1,25(OH)(2)D(3), whereas LAC67a and LAC67b were not effective. We examined the expression of endogenous VDR target genes and the nuclear protein levels of VDR and cofactors in several cell lines, including cells derived from intestine, bone, and monocytes, and found that the vitamin D(3) derivatives act as cell type-selective VDR modulators. The data indicate that side chain modification is useful in the development of VDR antagonists and tissue-selective modulators. Further elucidation of the molecular mechanisms of action of selective VDR modulators will be essential for their clinical application.

Cotylenin A-induced differentiation is independent of the transforming growth factor-beta signaling system in human myeloid leukemia HL-60 cells.

Cotylenin A, which has been isolated as a plant growth regulator, potently induces the differentiation of human myeloid leukemia cells. Treatment of HL-60 cells with a combination of transforming growth factor (TGF)-beta and 1alpha, 25-dihydroxyvitamin D(3) (VD3) resulted in increased differentiation compared to separate treatments, but TGF-beta did not affect the cotylenin A-induced differentiation of HL-60 cells. It is possible that the signal transduction pathway used by cotylenin A for inducing the differentiation of leukemia cells is the same as that used by TGF-beta. However, cotylenin A did not affect the expression of TGF superfamily or Smad genes in HL-60 cells. Treatment with neutralizing anti-TGF-beta antibody or an inhibitor of TGF-beta signaling did not inhibit cotylenin A-induced differentiation, although VD3-induced differentiation was significantly suppressed by these treatments. The subcellular distribution of Smad3 was also unaffected by cotylenin A. These results suggest that the cotylenin A-induced differentiation of leukemia cells is independent of the TGF-beta signaling system, although TGF-beta acts as an autocrine mediator of the growth arrest and differentiation of leukemia cells induced by VD3 and other inducers.