Diverging fates of cells of origin in acute and chronic leukaemia

• Published in: EMBO molecular medicine Vol. 4; no. 4; pp. 283 - 297
• Main Authors: Kovacic, Boris, Hoelbl, Andrea, Litos, Gabriele, Alacakaptan, Memetcan, Schuster, Christian, Fischhuber, Katrin M., Kerenyi, Marc A., Stengl, Gabriele, Moriggl, Richard, Sexl, Veronika, Beug, Hartmut
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2012; WILEY‐VCH Verlag; EMBO Press; WILEY-VCH Verlag
• Subjects: Abl gene; Acute lymphoblastic leukemia; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; BCR gene; BCR protein; B‐lymphoid differentiation; Cancer; cancer stem cells; Cell differentiation; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; cells of origin of cancer; Cloning; Genotype & phenotype; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Humans; leukaemia; Leukemia; Leukemia, Basophilic, Acute - metabolism; Leukemia, Basophilic, Acute - pathology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Lymphocytes B; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Phenotypes; Research Article; Stat5 protein; STAT5 Transcription Factor - metabolism; Stem cells; Stochasticity; cells of origin of cancer; B‐lymphoid differentiation; leukaemia; cancer; cancer stem cells
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201100208

The large difference in phenotypes among tumour populations may stem from the stochastic origin of tumours from distinct cells – tumour cells are assumed to retain the phenotypes of the cells from which they derive. Yet, functional studies addressing the cellular origin of leukaemia are lacking. Here we show that the cells of origin of both, BCR/ABL‐induced chronic myeloid (CML) and B‐cell acute lymphoid leukaemia (B‐ALL), resemble long‐term haematopoietic stem cells (LT‐HSCs). During disease‐maintenance, CML LT‐HSCs persist to function as cancer stem cells (CSCs) that maintain leukaemia and require signalling by the transcription factor STAT5. In contrast, B‐ALL LT‐HSCs differentiate into CSCs that correspond to pro‐B cells. This transition step requires a transient IL‐7 signal and is lost in IL‐7Rα‐deficient cells. Thus, in BCR/ABLp185
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B‐ALL and BCR/ABLp210
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CML, the final phenotype of the tumour as well as the abundance of CSCs is dictated by diverging differentiation fates of their common cells of origin.