Induction of acute lymphocytic leukemia differentiation by maintenance therapy

Lin, T. L.; Vala, M. S.; Barber, J. P.; Karp, J. E.; Smith, B. D.; Matsui, W.; Jones, R. J.
September 2007
Leukemia (08876924);Sep2007, Vol. 21 Issue 9, p1915
Academic Journal
journal article
Despite extensive study in many malignancies, maintenance therapy has clinically benefited only two diseases: acute lymphocytic leukemia (ALL) and acute promyelocytic leukemia (APL). ALL maintenance therapy utilizes low-dose 6-mercaptopurine (6MP) and methotrexate (MTX), while maintenance in APL primarily consists of all-trans-retinoic acid (ATRA). 6MP and MTX as used in ALL are also now usually added to maintenance ATRA for APL, based on data suggesting an improved disease-free survival. Although the mechanism of action of MTX and 6MP as maintenance is unknown, low-dose cytotoxic agents are potent inducers of differentiation in vitro. Thus, we studied whether maintenance therapy in ALL, like ATRA in APL, may be inducing terminal differentiation of ALL progenitors. The APL cell line NB4, the ALL cell lines REH and RS4;11, and patients' ALL blasts were incubated with ATRA, 6MP, and MTX in vitro. All three drugs inhibited the clonogenic growth of the APL and ALL cell lines without inducing immediate apoptosis, but associated with induction of phenotypic differentiation. The three drugs similarly upregulated lymphoid antigen expression, while decreasing CD34 expression, on patients' ALL blasts. These data suggest that induction of leukemia progenitor differentiation plays an important role in the mechanism of action of maintenance therapy in ALL.


Related Articles

  • A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity. Chen, S.-H.; Yang, W.; Fan, Y.; Stocco, G.; Crews, K. R.; Yang, J. J.; Paugh, S. W.; Pui, C.-H.; Evans, W. E.; Relling, M. V. // Leukemia (08876924);Jan2011, Vol. 25 Issue 1, p66 

    Asparaginase is an important component for treatment of childhood acute lymphoblastic leukemia (ALL). The basis for interindividual differences in asparaginase sensitivity remains unclear. To comprehensively identify genetic variants important in the cytotoxicity of asparaginase, we used a...

  • Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia. DiJoseph, J. F.; Dougher, M. M.; Armellino, D. C.; Evans, D. Y.; Damle, N. K. // Leukemia (08876924);Nov2007, Vol. 21 Issue 11, p2240 

    CMC-544 (inotuzumab ozogamicin) is a CD22-specific cytotoxic immunoconjugate of calicheamicin intended for the treatment of B-lymphoid malignancies. This preclinical study investigated antitumor activity of CMC-544 against CD22+ acute lymphoblastic leukemia (ALL). CMC-544 inhibited in vitro...

  • Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. Johnson, Søren M.; Torrice, Chad D.; Bell, Jessica F.; Monahan, Kimberly B.; Qi Jiang; Yong Wang; Ramsey, Matthew R.; Jian Jin; Kwok-Kin Wong; Lishan Su; Daohong Zhou; Sharpless, Norman E.; Johnson, Søren M; Jiang, Qi; Wang, Yong; Jin, Jian; Wong, Kwok-Kin; Su, Lishan; Zhou, Daohong // Journal of Clinical Investigation;Jul2010, Vol. 120 Issue 7, p2528 

    Total body irradiation (TBI) can induce lethal myelosuppression, due to the sensitivity of proliferating hematopoietic stem/progenitor cells (HSPCs) to ionizing radiation (IR). No effective therapy exists to mitigate the hematologic toxicities of TBI. Here, using selective and structurally...

  • Human A1, a Bcl-2-related gene, is induced in leukemic cells by cytokines as well as differentiating factors. Moreb, J S; Schweder, M // Leukemia (08876924);Jul97, Vol. 11 Issue 7, p998 

    Based on previously published observations regarding the protective effects of interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) against gamma radiation, alkylating agents and ultraviolet radiation, we hypothesized that the protection against such DNA damaging treatments can be...

  • Favorable toxicity profile of raltitrexed in elderly patients treated for colorectal cancer: a case series. Franchi, F.; Pastore, C.; Caporale, A.; Fabiani, O.; Rossi, L.; Seminara, P. // Gerontology;Sep/Oct2003, Vol. 49 Issue 5, p324 

    Background: Age-related physiological changes may lead to an increased toxicity of chemotherapy in the elderly, thus making tumor treatment difficult in this increasing subset of patients.Objective: Since many trials claimed a favorable therapeutic index with...

  • Notch signaling in mammalian hematopoietic stem cells. Pajcini, K V; Speck, N A; Pear, W S // Leukemia (08876924);Oct2011, Vol. 25 Issue 10, p1525 

    Notch is a crucial cell signaling pathway in metazoan development. By means of cell-cell interactions, Notch signaling regulates cellular identity, proliferation, differentiation and apoptosis. Within the last decade, numerous studies have shown an important role for this pathway in the...

  • HIV-1 Rev-binding protein accelerates cellular uptake of iron to drive Notch-induced T cell leukemogenesis in mice. Khwaja, Shariq S.; Hudan Liu; Caili Tong; Fang Jin; Pear, Warren S.; van Deursen, Jan; Bram, Richard J.; Liu, Hudan; Tong, Caili; Jin, Fang // Journal of Clinical Investigation;Jul2010, Vol. 120 Issue 7, p2537 

    Somatic activating mutations in Notch1 contribute to the pathogenesis of T cell acute lymphoblastic lymphoma (T-ALL), but how activated Notch1 signaling exerts this oncogenic effect is not completely understood. Here we identify HIV-1 Rev-binding protein (Hrb), a component of the...

  • Bone marrow stem cell mobilization in stroke: a 'bonehead' may be good after all! Borlongan, C V // Leukemia (08876924);Nov2011, Vol. 25 Issue 11, p1674 

    Mobilizing bone cells to the head, astutely referred to as 'bonehead' therapeutic approach, represents a major discipline of regenerative medicine. The last decade has witnessed mounting evidence supporting the capacity of bone marrow (BM)-derived cells to mobilize from BM to peripheral blood...

  • TEL-AML1 fusion transcript designates a favorable outcome with an intensified protocol in childhood acute lymphoblastic leukemia. Avigad, S; Kuperstein, G; Zilberstein, J; Liberzon, E; Stark, B; Gelernter, I; Kodman, Y; Luria, D; Ash, S; Stein, J; Goshen, Y; Yaniv, I; Cohen, I J; Zaizov, R // Leukemia (08876924);Mar99, Vol. 13 Issue 3, p481 

    Analyzes B-lineage childhood acute lymphoblastic leukemia patients for the acute myelocytic leukemia fusion transcript at diagnosis and correlates the findings with duration of remission. Details of patients diagnosed; Event free survival rates of patients; Treatment protocols used in the study.


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics