Fibrinogen — proteolysis in acute myelogenous leukemia (AML)

Summary Fibrinopeptides were measured as direct indices of thrombin, plasmin and elastase in plasma samples obtained from patients with AML. Peptide patterns observed were consistent with spontaneous or drug induced plasmin-specific fibrinogenolysis (AML FAB M 1/3), elastase mediated proteolysis (AML FAB M 3/4) or DIC (AML FAB M 4/5). DIC was also observed in septic, agranulocytotic patients.Presented in part at the XX Congress of the International Society of Hematology, September 1–7, 1984, Buenos Aires, Argentina; Supported by Deutsche Forschungsgemeinschaft (grant Ec 58-3/2)This paper is dedicated to the memory of Dr. H. L. Nossel, who most generously supplied reagents for this studyThe doctoral thesis of Michael Koch is partly presented in this work     

TIM-3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells

Acute myelogenous leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), which represent the ultimate therapeutic target for AML. Recent studies have identified several AML LSC-specific surface antigens as candidate targets of therapeutic molecules. T cell immunoglobulin mucin-3 (TIM-3) is expressed on LSCs in most types of AML, with the exception of acute promyelocytic leukemia, but not on normal hematopoietic stem cells (HSCs). In xenograft models reconstituted with human AML LSCs or HSCs, an anti-human TIM-3 mouse IgG2a antibody with cytotoxic activities eradicates AML LSCs in vivo, but does not affect normal human hematopoiesis. Thus, TIM-3 is a promising therapeutic target for the eradication of AML LSCs.     

Negative effect of CTLA-4 on induction of T-cell immunity in vivo to B7-1+, but not B7-2+, murine myelogenous leukemia

B7 molecules provide important costimulatory signals to T cells, and B7 genes have been introduced into B7-negative tumor cells to enhance their immunogenicity. However, the role of B7 molecules in inducing tumor immunity is controversial because of conflicting results and reports of differential signaling through the B7 molecules and their ligands CD28 and CTLA-4. In this study, we compared the effect of B7-1 (CD80) and B7-2 (CD86) on the induction of T-cell immunity to C1498, a murine myelogenous leukemia. When cultured with exogenous cytokines in vitro, C1498/B7-1 and C1498/B7-2 induced syngeneic CD8+ T cells to kill parental C1498. In vivo, C1498/B7-1 grew progressively after subcutaneous injection, whereas C1498/B7-2 completely regressed after transient growth in naive mice. Spontaneous rejection of C1498/B7-2 resulted in immunity to challenge doses of C1498 and C1498/B7-1. Antibody-depletion studies in vivo showed that CD8+ T cells rejected C1498/B7-2, whereas only natural killer cells affected the growth of C1498/B7-1. Two approaches were used to determine whether preferential interaction of B7-1 with CTLA-4 contributed to the failure of C1498/B7-1 to activate CD8+ T cells in vivo. First, CTLA-4 specific monoclonal antibody was used to block B7-1-CTLA-4 interaction. Second, CTLA-4 deletional mutant (-/-) bone marrow chimeras were used as tumor hosts. In both systems, there was a significant increase in the rate of rejection of C1498/B7-1 tumors. Resistance to C1498/B7-1 in CTLA-4(minus sign/minus sign) hosts was mediated by CD8+ T cells. Blocking or deletion of CTLA-4 did not affect the growth of parental C1498, indicating that B7-1 was important for the induction of CD8+ T-cell immunity in the absence of CTLA-4.     

Lessons from models of murine erythroleukemia to acute myeloid leukemia (AML): proof-of-principle of co-operativity in AML

The models of acute erythroleukemia caused in mice by the Friend retrovirus SFFV (spleen focus forming virus) and the Spi-1/PU.1 transgenesis provide considerable information to help to understand the molecular mechanisms underlying the multi-stage nature of leukemia. Leukemogenesis in these murine models is initiated from an acute hyperplasia of erythroid progenitor cells followed later on by a blastic crisis. This review highlights recent findings demonstrating the key roles of the co-operation of two mutations occurring during leukemic progression, a mutation interfering with differentiation and a mutation conferring a proliferative advantage to cells. Through their multi-step evolution, these mouse erythroleukemia models resemble the two phases of human acute myeloid leukemia (AML). The findings we discuss provide evidence for similar molecular mechanisms involved in the evolution of leukemia in mice and men.     

Treatment strategies in acute myeloid leukemia (AML)

Summary Chemotherapy remains the backbone of treatment in AML. Of all adult patients 65% go into remission and have a chance of longer survival and of even being cured. Among the responders, 25% can be cured by intensive and long-term chemotherapy. Since the effect of chemotherapy appears not to be limited to a special period of time, its antileukemic and curative potential could be further exploited by multiple-step chemotherapy combining double induction, intensified consolidation and long-term maintenance. Improved antimicrobial treatment and the use of hematopoietic growth factors may help making multiple-step chemotherapy practicable, thereby increasing the cure rate in AML.The studies of the AML Cooperative Group (AMLCG) are supported by grants OIZP 0123 and 8701 of the Ministry of Research and Technology of the Federal Republic of GermanyDedicated to Professor Dr. Drs. h.c. Franz Büchner on his 95th birthday     

Treatment strategies in acute myeloid leukemia (AML)

Summary The strategy for treatment of relapsed or refractory acute myeloid leukemia must primarily be based on the patient's age and clinical condition as well as on the stage of the disease. Accordingly, the general decision between an intensive approach including high-dose chemotherapy or possibly immediate allogeneic bone marrow transplantation versus less-aggressive palliative treatment will precede the selection of the most appropriate salvage regimen. In patients qualifying for intensive second-line chemotherapy the duration of the first remission and the number of relapses provide the means to discriminate between refractoriness or maintained responsiveness to conventional protocols. More than 50% of patients with first relapses after 6–12 months remission duration will respond to standard therapy again and should therefore not be entered on investigational agents with unproven antileukemic activity. The latter seems deeply warranted, on the other hand, for early relapses, second recurrences and resistant first relapses with a remission rate of less than 30% after conventional regimens. These guidelines not only provide an objective rationale for selecting the most appropriate strategy at relapse in individual patients. Furthermore, they facilitate interstudy comparisons and a better judgement of different treatment protocols.     

In vitro effect of P-glycoprotein (P-gp) modulators on drug sensitivity of leukemic progenitors (CFU-L) in acute myelogenous leukemia (AML).

Cyclosporine A (CyA), a potent reversant of multidrug resistance (mdr), was studied for its effects on the sensitivity of leukemic progenitors (leukemia colony-forming units, CFU-L) to daunorubicin (DNR) and mitoxantrone. CyA was first compared to verapamil and cefoperazone for reversion of mdr in the mdr1+ cell line K562/DOX. A dramatic increase of sensitivity to 10(-6) M DNR was noted with CyA (0.5 and 1 microgram/ml) and verapamil (1 and 5 micrograms/ml), but not for cefoperazone (0.3 and 0.6 mg/ml). The sensitivity of K562/DOX to 10(-6) M mitoxantrone was also slightly enhanced by CyA. The change in CFU-L drug sensitivity in the presence of CyA was then tested in 12 relapsing/resisting patients and in 3 untreated patients with acute myelogenous leukemia (AML). No change in CFU-L sensitivity to DNR was noted, despite the presence of a subset of P-glycoprotein positive (P-gp+) cells in three out of the ten evaluable cases. Among the six evaluable cases tested with mitoxantrone and CyA, an increase of 50% in CFU-L sensitivity to mitoxantrone was noted in one (of three) P-gp+ patient. These data suggest that the CFU-L in AML rarely expressed the P-gp and that other mechanisms of drug resistance could be involved in AML.     

Circulating T cells in patients with untreated acute myelogenous leukemia are heterogeneous and can be activated through the CD3/TCR complex

T lymphocyte defects may contribute to the immune insufficiency seen in acute myelogenous leukemia (AML). We therefore characterized the T cell system for untreated AML patients. T lymphocyte subsets were analyzed by flow cytometry for 45 AML patients. The in vitro interferon-gamma (IFNgamma) release in response to stimulation with anti-CD3 plus anti-CD28 in the presence of autologous AML cells was examined for 31 patients. The majority of circulating lymphocytes were CD3(+)T cells, and CD19(+)B cells usually constituted < 10% of the lymphocytes. Most T cells expressed the alphabeta T cell receptor (TCRalphabeta(+)), and only a minority of the cells was TCRgammadelta(+). Both CD4(+) and CD8(+)T cells were detected, the CD4:CD8 ratio showed a wide variation but was generally >1.0. The majority of CD4(+) and CD8(+)T cells were CD45RA(+) cells. The T cells could be stimulated to release IFNgamma in response to anti-CD3 plus anti-CD28 ligation even in the presence of excess autologous AML blasts, and for a subset of patients (6 of 27) these IFNgamma levels could be further increased by the novel protein kinase C (PKC) agonist PEP005. In conclusion, circulating T cells in patients with untreated AML are mainly CD4(+) or CD8(+) TCRalphabeta(+); both CD45RA(+) and CD45R0(+) can be detected, and these cells can be activated through the CD3/TCR complex even in the presence of excess AML cells. For a subset of patients T cell responsiveness can be further increased by targeting PKC and these data therefore suggest that T cell function is not inhibited in AML patients.     

Prediction of therapy-related acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after autologous bone marrow transplant (ABMT) for lymphoma

Therapy-related acute myelogenous leukemia and myelodysplastic syndrome (t-AML/MDS) are being reported with increasing frequency as a complication of ABMT for Hodgkin's disease and non-Hodgkin's lymphoma. At present there is no method available to predict who is at risk or is destined to develop this nearly universally fatal disorder. We therefore investigated whether clonal growth of cells is predictive of the development of t-AML/MDS. In a patient who developed secondary AML/MDS 18 months after ABMT, X-linked clonality analysis at the human androgen receptor locus was performed on serial banked samples, and documented transition from polyclonal to clonal hematopoiesis. Clonal cells could be identified 6 months after transplant (1 year prior to the diagnosis of t-AML/MDS), at a time when there was no morphologic or clinical evidence of disease. Clonality analysis can be predictive of the development of t-AML/MDS after ABMT and may offer important insights into associated risk factors and strategies to minimize the risk of t-AML/MDS. Am. J. Hematol. 56:45–51, 1997. © 1997 Wiley-Liss, Inc.     

The t(8;21) chromosomal translocation in acute myelogenous leukemia modifies intranuclear targeting of the AML1/CBFalpha2 transcription factor

Targeting of gene regulatory factors to specific intranuclear sites may be critical for the accurate control of gene expression. The acute myelogenous leukemia 8;21 (AML1/ETO) fusion protein is encoded by a rearranged gene created by the ETO chromosomal translocation. This protein lacks the nuclear matrix-targeting signal that directs the AML1 protein to appropriate gene regulatory sites within the nucleus. Here we report that substitution of the chromosome 8-derived ETO protein for the multifunctional C terminus of AML1 precludes targeting of the factor to AML1 subnuclear domains. Instead, the AML1/ETO fusion protein is redirected by the ETO component to alternate nuclear matrix-associated foci. Our results link the ETO chromosomal translocation in AML with modifications in the intranuclear trafficking of the key hematopoietic regulatory factor, AML1. We conclude that misrouting of gene regulatory factors as a consequence of chromosomal translocations is an important characteristic of acute leukemias.     

Cerebellar myeloblastoma formation in CD7-positive, neural cell adhesion molecule (CD56)-positive acute myelogenous leukemia (M1)

 We present a first report of a CD7⁺ acute myelogenous leukemia patient who developed intracranial myeloblastomas. The patient was neurologically normal on physical examination at presentation. The peripheral leukocyte count was extremely high (203.6×10⁹/l). The blasts expressed CD7 and CD56 (neural cell adhesion molecule) in addition to CD13, CD33, CD34, and HLA-DR. The karyotype of bone marrow cells was normal. The patient was diagnosed as having acute myelogenous leukemia (AML, M1). Following a short period of complete remission, bone marrow relapse and meningeal leukemia occurred, and the patient died of respiratory failure. Autopsy revealed that blasts had invaded the subarachnoid space and cerebellum, and two myeloblastomas were found in the cerebellar hemisphere. Both CD7⁺ and CD56⁺ AML have been reported to have a high incidence of central nervous system involvement. CD7⁺ CD56⁺ AML calls for prophylaxis of central nervous system leukemia. Received: 2 May 1997 / Accepted: 17 July 1997     

Advanced acute myelogenous leukaemia (AML) during HAART-treated HIV disease, manifesting initially as a thyroid mass

A rare case report of acute myelogenous 46 XY, inv(16)(p13q22) leukaemia occurring in a patient with his HIV infection controlled by highly active antiretroviral therapy is reported, in the context of a review of the available literature evidences. The initial localization as an isolated thyroid mass has no clinical equivalents to date. Although at its initial presentation the haematological disease had a very advanced (M5) stage expressing a predominant monocytic phenotype, two 1-week cytotoxic chemotherapy cycles carried out with cytarabin-daunorubicin, achieved complete remission (as assessed by combined diagnostic imaging, and repeated bone marrow studies). At the present 11-month follow-up time, eventual bone marrow transplantation is under evaluation, since the chromosomal translocation was still present. A such favourable clinical response to acute, advanced myelogenous leukaemia with an insidious recognition is considered infrequent, especially in the setting of HIV disease.