Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation

Abstract

New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia.

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Figure 1: Fasting selectively inhibits ALL development.
Figure 2: Fasting inhibits B-ALL development in both early and late stages.
Figure 3: Fasting upregulates LEPR expression and its downstream signaling.
Figure 4: Attenuated LEPR signaling is essential for ALL development, and fasting does not inhibit B-ALL development in the absence of LEPR.
Figure 5: LEPR inhibits B-ALL development by promoting leukemic cell differentiation through PRDM1.
Figure 6: Fasting and LEPR signaling inhibit human ALL development.

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References

  1. 1

    Hursting, S.D., Lavigne, J.A., Berrigan, D., Perkins, S.N. & Barrett, J.C. Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu. Rev. Med. 54, 131–152 (2003).

    CAS  PubMed  Google Scholar 

  2. 2

    Fontana, L. & Partridge, L. Promoting health and longevity through diet: from model organisms to humans. Cell 161, 106–118 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Mihaylova, M.M., Sabatini, D.M. & Yilmaz, O.H. Dietary and metabolic control of stem cell function in physiology and cancer. Cell Stem Cell 14, 292–305 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Bordone, L. & Guarente, L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat. Rev. Mol. Cell Biol. 6, 298–305 (2005).

    CAS  PubMed  Google Scholar 

  5. 5

    Longo, V.D. & Mattson, M.P. Fasting: molecular mechanisms and clinical applications. Cell Metab. 19, 181–192 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Kalaany, N.Y. & Sabatini, D.M. Tumours with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Di Biase, S. et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136–146 (2016).

    CAS  Article  Google Scholar 

  8. 8

    Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Cheng, C.W. et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell 14, 810–823 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Lee, C. et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med. 4, 124ra27 (2012).

    PubMed  PubMed Central  Google Scholar 

  11. 11

    Döhner, H., Weisdorf, D.J. & Bloomfield, C.D. Acute myeloid leukemia. N. Engl. J. Med. 373, 1136–1152 (2015).

    PubMed  Google Scholar 

  12. 12

    Inaba, H., Greaves, M. & Mullighan, C.G. Acute lymphoblastic leukaemia. Lancet 381, 1943–1955 (2013).

    PubMed  Google Scholar 

  13. 13

    Ntziachristos, P., Lim, J.S., Sage, J. & Aifantis, I. From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell 25, 318–334 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Kocabas, F. et al. Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells. Blood 120, 4963–4972 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Simsek, T. et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7, 380–390 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Zheng, J. et al. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485, 656–660 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Kang, X. et al. The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development. Nat. Cell Biol. 17, 665–677 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Park, J., Euhus, D.M. & Scherer, P.E. Paracrine and endocrine effects of adipose tissue on cancer development and progression. Endocr. Rev. 32, 550–570 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Park, J., Kusminski, C.M., Chua, S.C. & Scherer, P.E. Leptin receptor signaling supports cancer cell metabolism through suppression of mitochondrial respiration in vivo. Am. J. Pathol. 177, 3133–3144 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Zheng, J. et al. Ex vivo expanded hematopoietic stem cells overcome the MHC barrier in allogeneic transplantation. Cell Stem Cell 9, 119–130 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Zheng, J. et al. Profilin 1 is essential for retention and metabolism of mouse hematopoietic stem cells in bone marrow. Blood 123, 992–1001 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Deng, M. et al. A motif in LILRB2 critical for Angptl2 binding and activation. Blood 124, 924–935 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Sugihara, E. et al. Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor. Oncogene 31, 2849–2861 (2012).

    CAS  PubMed  Google Scholar 

  24. 24

    Weng, A.P. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004).

    CAS  Google Scholar 

  25. 25

    Krivtsov, A.V. et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818–822 (2006).

    CAS  Google Scholar 

  26. 26

    Somervaille, T.C. & Cleary, M.L. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 10, 257–268 (2006).

    CAS  PubMed  Google Scholar 

  27. 27

    Yan, M. et al. A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat. Med. 12, 945–949 (2006).

    CAS  PubMed  Google Scholar 

  28. 28

    Shapiro-Shelef, M. & Calame, K. Regulation of plasma-cell development. Nat. Rev. Immunol. 5, 230–242 (2005).

    CAS  PubMed  Google Scholar 

  29. 29

    Shi, W. et al. Transcriptional profiling of mouse B cell terminal differentiation defines a signature for antibody-secreting plasma cells. Nat. Immunol. 16, 663–673 (2015).

    CAS  PubMed  Google Scholar 

  30. 30

    Vaisse, C. et al. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat. Genet. 14, 95–97 (1996).

    CAS  PubMed  Google Scholar 

  31. 31

    Morris, D.L. & Rui, L. Recent advances in understanding leptin signaling and leptin resistance. Am. J. Physiol. Endocrinol. Metab. 297, E1247–E1259 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Weigle, D.S. et al. Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels. J. Clin. Endocrinol. Metab. 82, 561–565 (1997).

    CAS  PubMed  Google Scholar 

  33. 33

    Andò, S. & Catalano, S. The multifactorial role of leptin in driving the breast cancer microenvironment. Nat. Rev. Endocrinol. 8, 263–275 (2011).

    PubMed  Google Scholar 

  34. 34

    Khandekar, M.J., Cohen, P. & Spiegelman, B.M. Molecular mechanisms of cancer development in obesity. Nat. Rev. Cancer 11, 886–895 (2011).

    CAS  PubMed  Google Scholar 

  35. 35

    Chua, S.C. Jr. et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271, 994–996 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Chen, H. et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491–495 (1996).

    CAS  PubMed  Google Scholar 

  37. 37

    Coleman, D.L. & Hummel, K.P. The influence of genetic background on the expression of the obese (Ob) gene in the mouse. Diabetologia 9, 287–293 (1973).

    CAS  PubMed  Google Scholar 

  38. 38

    Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    CAS  PubMed  Google Scholar 

  39. 39

    Fantuzzi, G. & Faggioni, R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J. Leukoc. Biol. 68, 437–446 (2000).

    CAS  PubMed  Google Scholar 

  40. 40

    Boi, M., Zucca, E., Inghirami, G. & Bertoni, F. PRDM1/BLIMP1: a tumor suppressor gene in B and T cell lymphomas. Leuk. Lymphoma 56, 1223–1228 (2015).

    CAS  PubMed  Google Scholar 

  41. 41

    Hangaishi, A. & Kurokawa, M. Blimp-1 is a tumor suppressor gene in lymphoid malignancies. Int. J. Hematol. 91, 46–53 (2010).

    CAS  PubMed  Google Scholar 

  42. 42

    Ross, J.A. et al. Genetic variation in the leptin receptor gene and obesity in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 22, 3558–3562 (2004).

    CAS  PubMed  Google Scholar 

  43. 43

    Wheeler, E. et al. Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat. Genet. 45, 513–517 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Vishalakshi, N. et al. A comprehensive curated reaction map of leptin Signaling Pathway. J. Proteomics Bioinform. 4, 184–189 (2011).

    Google Scholar 

  45. 45

    Teras, L.R. et al. in Energy Balance and Hematologic Malignancies Vol. 5 1st edn. (eds. Mittelman, S.D. & Berger, N.A.) 1–69 (Springer, New York, 2012).

  46. 46

    Sheng, X. & Mittelman, S.D. The role of adipose tissue and obesity in causing treatment resistance of acute lymphoblastic leukemia. Front Pediatr. 2, 53 (2014).

    PubMed  PubMed Central  Google Scholar 

  47. 47

    Bifulco, M. & Malfitano, A.M. Comment on “the negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia.”. Haematologica 100, e118–e119 (2015).

    PubMed  PubMed Central  Google Scholar 

  48. 48

    Butturini, A.M. et al. Obesity and outcome in pediatric acute lymphoblastic leukemia. J. Clin. Oncol. 25, 2063–2069 (2007).

    PubMed  Google Scholar 

  49. 49

    Oeffinger, K.C. et al. Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 21, 1359–1365 (2003).

    PubMed  Google Scholar 

  50. 50

    Yun, J.P. et al. Diet-induced obesity accelerates acute lymphoblastic leukemia progression in two murine models. Cancer Prev. Res. (Phila.) 3, 1259–1264 (2010).

    CAS  Google Scholar 

  51. 51

    Myers, M.G. Jr., Leibel, R.L., Seeley, R.J. & Schwartz, M.W. Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol. Metab. 21, 643–651 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Pramanik, R., Sheng, X., Ichihara, B., Heisterkamp, N. & Mittelman, S.D. Adipose tissue attracts and protects acute lymphoblastic leukemia cells from chemotherapy. Leuk. Res. 37, 503–509 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Baskin, D.G. et al. Increased expression of mRNA for the long form of the leptin receptor in the hypothalamus is associated with leptin hypersensitivity and fasting. Diabetes 47, 538–543 (1998).

    CAS  PubMed  Google Scholar 

  54. 54

    Weng, A.P. et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 20, 2096–2109 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Nowak, D., Stewart, D. & Koeffler, H.P. Differentiation therapy of leukemia: 3 decades of development. Blood 113, 3655–3665 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Efficace, F. et al. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J. Clin. Oncol. 32, 3406–3412 (2014).

    CAS  PubMed  Google Scholar 

  57. 57

    Lo-Coco, F. et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 369, 111–121 (2013).

    CAS  PubMed  Google Scholar 

  58. 58

    Hurwitz, R. et al. Characterization of a leukemic cell line of the pre-B phenotype. Intl. J. Cancer. Journal international du cancer 23, 174–180 (1979).

    CAS  Google Scholar 

  59. 59

    Filshie, R., Gottlieb, D. & Bradstock, K. VLA-4 is involved in the engraftment of the human pre-B acute lymphoblastic leukaemia cell line NALM-6 in SCID mice. Br. J. Haematol. 102, 1292–1300 (1998).

    CAS  PubMed  Google Scholar 

  60. 60

    Zhang, C.C., Kaba, M., Iizuka, S., Huynh, H. & Lodish, H.F. Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation. Blood 111, 3415–3423 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Rocke, D.M. & Durbin, B. A model for measurement error for gene expression arrays. J. Comput. Biol. 8, 557–569 (2001).

    CAS  PubMed  Google Scholar 

  62. 62

    Dozmorov, I. & Centola, M. An associative analysis of gene expression array data. Bioinformatics 19, 204–211 (2003).

    CAS  PubMed  Google Scholar 

  63. 63

    Dozmorov, I. & Lefkovits, I. Internal standard-based analysis of microarray data. Part 1: analysis of differential gene expressions. Nucleic Acids Res. 37, 6323–6339 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Kamburov, A., Stelzl, U., Lehrach, H. & Herwig, R. The ConsensusPathDB interaction database: 2013 update. Nucleic Acids Res. 41, D793–D800 (2013).

    CAS  PubMed  Google Scholar 

  65. 65

    Krämer, A., Green, J., Pollard, J. Jr. & Tugendreich, S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics 30, 523–530 (2014).

    PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge the support by grants from the US National Institutes of Health 1R01CA172268 (C.C.Z.), Leukemia & Lymphoma Society Awards 1024-14 (C.C.Z.) and TRP-6024-14 (C.C.Z.), CPRIT RP140402 (C.C.Z.), 1R01HL089966 (L.J.H.), R01-DK55758 (P.E.S.) and RP140412 (P.E.S.).

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C.C.Z. and Z.L. designed experiments. C.C.Z. conceived the study. Z.L., J.X., G.W., J.S. and P.E.S. performed experiments and interpreted data. L.J.-S.H., X.K., Y.Z. and M.L. performed experiments. Z.L. and J.X. performed statistical analysis. R.C., W.C., J.F.A., T.S. and N.W. provided patient samples. The manuscript was written by C.C.Z. and Z.L. and contributed to by all authors.

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Correspondence to Cheng Cheng Zhang.

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The authors declare no competing financial interests.

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Lu, Z., Xie, J., Wu, G. et al. Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat Med 23, 79–90 (2017). https://doi.org/10.1038/nm.4252

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