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Differentiation induction as a treatment for hematologic malignancies

Oncogene volume 21, pages 3496–3506 (2002)Cite this article

In leukemic cell lines and primary cultures treatment with Biomodulators (hematopoietic growth factors, TGFβ, vitamin D, retinoic acid butyrates, free fatty acids, interferons) and cyclic nucleotides and Chemical agents (DMSO, histone deacetylase inhibitors (HDACi), HMBA, TPA, certain cytotoxic agents) alone, or in combination, results in a similar scenario during the process of induced differentiation. This typically includes a stochastic program of early influx of calcium, protein kinase C translocation and activation, G1 cell cycle arrest associated with p53 dependent or independent p21WAF1 induction, retinoblastoma protein hypophosphorylation, a decrease in growth-associated genes such as c-myc, c-myb, and an early increase in anti-apoptotic proteins (Rifkind et al., 1996; Scher et al., 1983b; Waxman, 2000). Thereafter an array of lineage differentiation specific gene expressions is followed by commitment to terminal cell division often with the expression of an apoptotic program (Altucci et al., 2001; Liu et al., 2000). The activation of specific signaling pathways are differentiation agent and cell type specific. Differentiation induction of hematologic malignant cells as well as normal hematopoeitic stem cell differentiation is mediated by a stochiometric ratio of transcription factors such as GATA-1 and PU-1 (Rekhtman et al., 1999) which broadly determine lineage and cooperate with more specific transcription factors such as RAR receptor and CEBP family members (Matushansky et al., 2000; Park et al., 1999; Tenen et al., 1997). Erythropoietin (EPO) induced erythrodifferentiation of leukemic cells is associated with GATA-1 induction and downregulation of PU-1 and other transcription factors that direct myeloid lineage during normal differentiation. Conversely, myeloid differentiation of A4 murine progenitor cells by GCSF or GMCSF increases RARα2 whereas erythrodifferentiation induced by EPO downregulates RARα2 (Zhu et al., 2001). Therefore, with appropriate stimulation the regulatory pathways involved in hematopoeitic differentiation can be re-activated in hematopoeitic malignant cells. Targeting the molecular defect that interferes with the normal regulatory pathway may provide such a stimulus and serve as the basis of differentiation therapy. A paradigm for differentiation therapy of hematologic malignancies is provided by the successful development of all trans-retinoic acid (RA) therapy and elucidation of its molecular mechanism in acute promyelocytic leukemia (APL).

For many years, treatment of APL was restricted to aggressive chemotherapy that, when successful, eliminated the malignant clone. In 1988, a Chinese group reported dramatic clinical responses to oral therapy with RA, an active form of vitamin A (Huang et al., 1988). They, and subsequently researchers in France and the USA, demonstrated a novel mechanism by which these responses were obtained (Castaigne et al., 1990; Warrell et al., 1991). RA induces APL blasts to terminally differentiate along a neutrophilic pathway, without any evidence of direct cytotoxic effects. Although clinical relapse occurs commonly after treatment with RA alone, large multicenter randomized trials have demonstrated that RA in combination with chemotherapy results in a higher rate of durable remission and survival than chemotherapy alone, with a potential cure in nearly 70% of patients (Fenaux et al., 1994; Sanz et al., 2000). Thus, treatment of APL with retinoids provides the first dramatic demonstration of efficacy of differentiation therapy in an advanced malignancy.

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Samuel Waxman – NIH R01 CA85748, NIH R01 CA59936, Samuel Waxman Cancer Research Foundation; Wilson H Miller – Career Award, Scientist of the Canadian Institutes of Health Research. The critical reading of this manuscript by George Acs, Yongkui Jing and Liliana Ossowski is greatly appreciated.

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    Wilson H Miller Jr

  2. Department of Medicine, Mount Sinai School of Medicine, New York, 10029, NY, USA

    Samuel Waxman

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Miller Jr, W., Waxman, S. Differentiation induction as a treatment for hematologic malignancies. Oncogene 21, 3496–3506 (2002). https://doi.org/10.1038/sj.onc.1205328

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