Cancer Cell
Previews prognosis and treatment of MDS/AML. They can be founder events and are associated with a preleukemic state. Further studies of the mechanisms and functions of DDX41 and other members of the RNA helicases family in hematopoiesis and leukemogenesis are warranted and may ultimately lead to approaches of therapeutic targeting of these proteins. REFERENCES Antony-Debre´, I., Manchev, V.T., Balayn, N., Bluteau, D., Tomowiak, C., Legrand, C., Langlois, T.,
Bawa, O., Tosca, L., Tachdjian, G., et al. (2015). Blood 125, 930–940. Ding, L., Ley, T.J., Larson, D.E., Miller, C.A., Koboldt, D.C., Welch, J.S., Ritchey, J.K., Young, M.A., Lamprecht, T., McLellan, M.D., et al. (2012). Nature 481, 506–510. Fuller-Pace, F.V. (2013). RNA Biol. 10, 121–132. Jankowsky, E. (2011). Trends Biochem. Sci. 36, 19–29. Pabst, T., Eyholzer, M., Haefliger, S., Schardt, J., and Mueller, B.U. (2008). J. Clin. Oncol. 26, 5088– 5093. Pandolfi, A., Barreyro, L., and Steidl, U. (2013). Stem Cells Transl. Med. 2, 143–150.
Polprasert, C., Schulze, I., Sekeres, M.A., Makishima, H., Przychodzen, B., Hosono, N., Singh, J., Padgett, R.A., Gu, X., Phillips, J.G., et al. (2015). Cancer Cell 27, this issue, 658–670. Preudhomme, C., Renneville, A., Bourdon, V., Philippe, N., Roche-Lestienne, C., Boissel, N., Dhedin, N., Andre´, J.M., Cornillet-Lefebvre, P., Baruchel, A., et al. (2009). Blood 113, 5583– 5587. West, A.H., Godley, L.A., and Churpek, J.E. (2014). Ann. N Y Acad. Sci. 1310, 111–118. Xu, Y.Z., Newnham, C.M., Kameoka, S., Huang, T., Konarska, M.M., and Query, C.C. (2004). EMBO J. 23, 376–385.
Convert and Conquer: The Strategy of Chronic Myelogenous Leukemic Cells Simo´n Me´ndez-Ferrer,1,2,* Marı´a Garcı´a-Ferna´ndez,1 and Carlos L.F. de Castillejo1 1Stem
Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain Institute and Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge Biomedical Campus, CB2 0PT Cambridge, UK *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2015.04.012 2Stem Cell
Emerging evidence is contributing to explain how leukemias disrupt normal blood cell production. In this issue of Cancer Cell, Welner and colleagues show that, during the development of chronic myeloid leukemia, mutated cells transform normal hematopoietic progenitors into ‘‘leukemic like’’ cells through IL-6 secretion, proposing a new cellular target. Classical cancer therapies target the malignant cells. However, the environment surrounding the tumors, referred to as ‘‘niche,’’ during cancer development and progression is gaining increased attention. Many efforts are now directed toward understanding the relationships between the tumor and its supporting cells (e.g., stromal cells), which have become a novel target for therapies. This also applies to blood proliferative disorders, such as myeloproliferative neoplasms (MPNs), in which the interactions between tumoral and stromal cells are critical for disease progression both at the hematopoietic stem cell (HSC) and progenitor level (Arranz et al., 2014; Krause et al., 2013; Schepers et al., 2013). However, leukemic stem cell niches might be different in chronic and acute myeloid leukemias. The Scadden
group has demonstrated that activation of osteoblastic cells by parathyroid hormone attenuates chronic myelogenous leukemia (CML), but enhances instead MLL-AF9 oncogene-induced acute myeloid leukemia (Krause et al., 2013). Using a JAK2V617F murine model, we have recently shown that nestin+ mesenchymal stem cells (MSCs) play a pivotal role in regulating the proliferation of mutant MPN HSCs. IL-1b secreted by mutant HSCs induces neural damage to the niche, leading to a marked reduction in nestin+ MSCs, uncontrolled mutant HSC proliferation, and subsequent disease progression (Arranz et al., 2014). Bone marrow stromal cells have been proposed to secrete factors that protect JAK2V617F cells from JAK2 inhibitors (Manshouri et al., 2011). Additionally, the
Passegue´ group has recently demonstrated that CML cells induce expansion of osteoblastic precursors that poorly support normal hematopoietic progenitors (Schepers et al., 2013). CML is an MPN that originates in a mutated hematopoietic stem/progenitor cell (HSPC) carrying the t(9;22)(q34;q11) translocation. This mutation leads to the expression of the BCR/ABL fusion protein, a constitutively active tyrosine kinase that promotes the growth of mutated HSCs and their progeny. In humans, CML presents first with a chronic phase in which differentiated myeloid cells accumulate. This is followed by a short accelerated phase that precedes a rapid blast phase when symptoms aggravate as myeloid cells fail to mature and fully differentiate (Savona and Talpaz, 2008).
Cancer Cell 27, May 11, 2015 ª2015 Elsevier Inc. 611
Cancer Cell
Previews
Figure 1. Model of Manifestation and Progression of Myeloproliferative Neoplasms (1) Myeloproliferative neoplasm (MPN) is originated by a mutated hematopoietic stem cell (Leuk HSC) with increased survival and proliferative capacity. Mutated HSCs secrete IL-1b, which causes damage on sympathetic nervous system (SNS) nerve terminals and MSC apoptosis. (2) Deficiently controlled by the niche, Leuk HSCs generate more mutated leukemic progenitors (Leuk prog) and myeloid cells. (3) Leukemic cells produce IL-6, which transforms normal leukemia-exposed progenitor cells into ‘‘leukemic-like’’ cells, boosting the proliferation of myeloid cells at the expense of lymphocytes. (4) Both Leuk prog and leukemia-exposed progenitors secrete inflammatory cytokines that stimulate disease progression. Osteoblastic cells (OBs) proliferate and become less supportive for normal hematopoietic progenitors.
During the chronic phase of CML, the accumulation of leukemic cells in the bone marrow impairs normal hematopoiesis. HSPCs progressively leave the bone marrow and infiltrate the spleen. If not successfully managed, the reduced number of fully mature, functional blood and immune cells can cause anemias, bleedings, or infections. The displacement of normal hematopoiesis was previously thought to be the passive result of the rapid expansion of leukemic cells in the bone marrow cavity (Savona and Talpaz, 2008). However, the idea of mere movement of normal cells due to outgrowth of leukemic cells is not supported by extramedullary hematopoiesis occurring also with low tumor burden. Alternatively, leukemic cells can modify their niches and outcompete normal HSPCs (Arranz et al., 2014; Colmone et al., 2008; Krause et al., 2013; Schepers et al., 2013; Zhang et al., 2012).
In this issue of Cancer Cell, Welner et al. (2015) propose an alternative explanation for this long-standing question. They show that leukemic cells can directly transform non-mutated HPSCs into functional ‘‘leukemic-like’’ progenitor cells. Welner et al. (2015) used the Scl/Tal1tTA x TRE-BCR/ABL double transgenic mouse model of inducible CML (upon tetracycline removal), previously utilized by this and other groups. To study the interaction between mutated and nonmutated hematopoietic cells—a novel aspect that is also more similar to the human disease—the authors transplanted wild-type hematopoietic cells expressing the CD45.1 isotype together with either SCL-tTA x BCR-ABL CD45.2 leukemic cells or wild-type CD45.2 control cells into lethally irradiated CD45.1 mice. Following transplantation, mice were administered tetracycline for 16 weeks
612 Cancer Cell 27, May 11, 2015 ª2015 Elsevier Inc.
to establish hematopoietic homeostasis and then CML was induced by tetracycline removal. Taking advantage of these chimeric mice, the authors could study the interaction between mutated and non-mutated ‘‘leukemic-exposed’’ cells. Surprisingly, non-mutated cells exposed to leukemic cells adopted some of their features, such as the excessive production of myeloid cells and the deficient generation of lymphoid cells. To understand the cause of this bias in myeloid/lymphoid lineage differentiation, the authors analyzed hematopoietic progenitors—defined as cells expressing the antigens c-kit (at high levels) and sca-1 but lacking expression of lineage markers expressed in mature hematopoietic cells (KSL)—short-term (ST)-HSCs (CD34+ Flt3 KSL cells), and long-term (LT)-HSCs (CD150+ CD48 KSL cells). Interestingly, leukemic-exposed progenitors or ST-HSCs, but not the leukemic-exposed HSCs, showed increased proliferation and accumulation. Subsequent experiments confirmed a clear progenitor bias toward production of myeloid cells at the expense of lymphoid lineages, resembling the mutated leukemic progenitors. However, that was not the case for HSCs, which showed instead impaired self-renewal and reduced capacity to reconstitute the hematopoietic system of transplanted secondary recipients. To investigate the mechanisms leading to these functional modifications, the researchers performed genome-wide gene profiling of purified control or leukemicexposed HSPCs. Interestingly, Gene Set Enrichment Analysis (GSEA) showed a BCR-ABL+ signature in leukemic-exposed progenitors that closely resembled that of mutated leukemic cells. Additionally, the transcriptome of leukemicexposed HSCs was consistent with deficient self-renewal and bone marrow engraftment. But how can leukemic cells make normal cells act alike? It was previously shown that CML generates an inflammatory environment (Reynaud et al., 2011; Kleppe et al., 2015). Welner et al. (2015) confirmed the increased production of the pro-inflammatory cytokines GM-CSF, IL-6, and IL-1a in the chimeric mice. Based on the known functions of each cytokine, the authors focused their attention on IL-6, which had been previously shown to modify
Cancer Cell
Previews leukemic cells (Reynaud et al., 2011). Could this cytokine also transform the function of the normal HSPCs? Consistent with the different effects of the leukemic cells on normal HSCs and progenitors, expression of the IL-6 receptor was found to be much higher in the latter. The authors went on to perform loss-of-function experiments using IL-6 blocking antibodies and an inducible Mx1-Cre;IL-6Raflox/flox system. Both the pharmacological blockade and genetic deletion experiments showed a complete yet transient phenotypic reversion in leukemic-exposed hematopoietic progenitors. Reduced IL-6 production and rescue of the induced leukemiclike phenotypes were also observed in chimeric mice treated with imatinib, the tyrosine-kinase inhibitor currently used to treat CML patients. To address the relevance to human disease, Welner et al. (2015) cultured adult bone marrow CD34+ cells mixed with bone marrow from either healthy subjects or CML patients, obtaining similar results as in the mouse model, i.e., increased IL-6 content and CD34+ cell proliferation, but decreased lymphoid production. These phenotypes were also reverted by IL-6 inhibition. A recent study has shown that both the mutated and non-mutated leukemicexposed hematopoietic cells produce inflammatory cytokines in MPN (Kleppe et al., 2015). This study found IL-6 to be
mainly secreted by the mutated cells. Although the mutations explored in the Welner et al. (2015) study and the Kleppe et al. (2015) study are different, parallels from both studies point toward a scenario in which IL-6 secretion by mutant cells transforms normal hematopoietic cells into leukemic-like cells. In summary, several alterations of normal bone marrow cells induced by mutated HSPCs are required for the manifestation and progression of MPN (Figure 1): (1) neuroglial damage in the bone marrow and induced apoptosis of HSC-niche forming nestin+ MSC, leading to uncontrolled proliferation of mutated HSCs (Arranz et al., 2014); (2) production of pro-inflammatory cytokines by leukemic and normal cells (Reynaud et al., 2011; Kleppe et al., 2015); (3) induction of some leukemic-like features in the normal hematopoietic progenitors (Welner et al., 2015); and (4) excessive proliferation of osteoblastic precursors that become less supportive for hematopoietic progenitors (Krause et al., 2013; Schepers et al., 2013). Targeting the non-mutated bone marrow cells therefore opens up an attractive door for the development of new therapeutic strategies. REFERENCES Arranz, L., Sa´nchez-Aguilera, A., Martı´n-Pe´rez, D., Isern, J., Langa, X., Tzankov, A., Lundberg, P.,
Muntio´n, S., Tzeng, Y.S., Lai, D.M., et al. (2014). Nature 512, 78–81. Colmone, A., Amorim, M., Pontier, A.L., Wang, S., Jablonski, E., and Sipkins, D.A. (2008). Science 322, 1861–1865. Kleppe, M., Kwak, M., Koppikar, P., Riester, M., Keller, M., Bastian, L., Hricik, T., Bhagwat, N., McKenney, A.S., Papalexi, E., et al. (2015). Cancer Discov 5, 316–331. Krause, D.S., Fulzele, K., Catic, A., Sun, C.C., Dombkowski, D., Hurley, M.P., Lezeau, S., Attar, E., Wu, J.Y., Lin, H.Y., et al. (2013). Nat. Med. 19, 1513–1517. Manshouri, T., Estrov, Z., Quinta´s-Cardama, A., Burger, J., Zhang, Y., Livun, A., Knez, L., Harris, D., Creighton, C.J., Kantarjian, H.M., and Verstovsek, S. (2011). Cancer Res. 71, 3831–3840. Reynaud, D., Pietras, E., Barry-Holson, K., Mir, A., Binnewies, M., Jeanne, M., Sala-Torra, O., Radich, J.P., and Passegue´, E. (2011). Cancer Cell 20, 661–673. Savona, M., and Talpaz, M. (2008). Nat. Rev. Cancer 8, 341–350. Schepers, K., Pietras, E.M., Reynaud, D., Flach, J., Binnewies, M., Garg, T., Wagers, A.J., Hsiao, E.C., and Passegue´, E. (2013). Cell Stem Cell 13, 285–299. Welner, R.S., Amabile, G., Bararia, D., Czibere, A., Yang, H., Zhang, H., De Figuereido-Pontes, L.L., Ye, M., Levantini, E., Di Ruscio, A., et al. (2015). Cancer Cell 27, this issue, 671–681. Zhang, B., Ho, Y.W., Huang, Q., Maeda, T., Lin, A., Lee, S.U., Hair, A., Holyoake, T.L., Huettner, C., and Bhatia, R. (2012). Cancer Cell 21, 577–592.
Defining the Molecular Landscape of Ependymomas Tenley C. Archer1,2 and Scott L. Pomeroy1,2,* 1Department
of Neurology, Boston Children’s Hospital, Harvard Medical School Institute of MIT and Harvard Harvard University, Cambridge, MA 02138, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2015.04.015 2Broad
Ependymomas have a variable prognosis. In this issue of Cancer Cell, Pajtler and colleagues identify nine subgroups of ependymoma using DNA methylation profiles. Two subgroups, predominately pediatric, are responsible for most of the mortality, with all others having nearly 100% overall survival after 5 years. For the past several decades, there has been little progress in the treatment of ependymomas. Currently, treatment is
largely restricted to maximal surgical resection and, in some cases, external beam radiation. The tumors do not con-
sistently respond to chemotherapy, and clinical behavior is not accurately predicted by histologic grade. Current
Cancer Cell 27, May 11, 2015 ª2015 Elsevier Inc. 613
Previews prognosis and treatment of MDS/AML. They can be founder events and are associated with a preleukemic state. Further studies of the mechanisms and functions of DDX41 and other members of the RNA helicases family in hematopoiesis and leukemogenesis are warranted and may ultimately lead to approaches of therapeutic targeting of these proteins. REFERENCES Antony-Debre´, I., Manchev, V.T., Balayn, N., Bluteau, D., Tomowiak, C., Legrand, C., Langlois, T.,
Bawa, O., Tosca, L., Tachdjian, G., et al. (2015). Blood 125, 930–940. Ding, L., Ley, T.J., Larson, D.E., Miller, C.A., Koboldt, D.C., Welch, J.S., Ritchey, J.K., Young, M.A., Lamprecht, T., McLellan, M.D., et al. (2012). Nature 481, 506–510. Fuller-Pace, F.V. (2013). RNA Biol. 10, 121–132. Jankowsky, E. (2011). Trends Biochem. Sci. 36, 19–29. Pabst, T., Eyholzer, M., Haefliger, S., Schardt, J., and Mueller, B.U. (2008). J. Clin. Oncol. 26, 5088– 5093. Pandolfi, A., Barreyro, L., and Steidl, U. (2013). Stem Cells Transl. Med. 2, 143–150.
Polprasert, C., Schulze, I., Sekeres, M.A., Makishima, H., Przychodzen, B., Hosono, N., Singh, J., Padgett, R.A., Gu, X., Phillips, J.G., et al. (2015). Cancer Cell 27, this issue, 658–670. Preudhomme, C., Renneville, A., Bourdon, V., Philippe, N., Roche-Lestienne, C., Boissel, N., Dhedin, N., Andre´, J.M., Cornillet-Lefebvre, P., Baruchel, A., et al. (2009). Blood 113, 5583– 5587. West, A.H., Godley, L.A., and Churpek, J.E. (2014). Ann. N Y Acad. Sci. 1310, 111–118. Xu, Y.Z., Newnham, C.M., Kameoka, S., Huang, T., Konarska, M.M., and Query, C.C. (2004). EMBO J. 23, 376–385.
Convert and Conquer: The Strategy of Chronic Myelogenous Leukemic Cells Simo´n Me´ndez-Ferrer,1,2,* Marı´a Garcı´a-Ferna´ndez,1 and Carlos L.F. de Castillejo1 1Stem
Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain Institute and Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge Biomedical Campus, CB2 0PT Cambridge, UK *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2015.04.012 2Stem Cell
Emerging evidence is contributing to explain how leukemias disrupt normal blood cell production. In this issue of Cancer Cell, Welner and colleagues show that, during the development of chronic myeloid leukemia, mutated cells transform normal hematopoietic progenitors into ‘‘leukemic like’’ cells through IL-6 secretion, proposing a new cellular target. Classical cancer therapies target the malignant cells. However, the environment surrounding the tumors, referred to as ‘‘niche,’’ during cancer development and progression is gaining increased attention. Many efforts are now directed toward understanding the relationships between the tumor and its supporting cells (e.g., stromal cells), which have become a novel target for therapies. This also applies to blood proliferative disorders, such as myeloproliferative neoplasms (MPNs), in which the interactions between tumoral and stromal cells are critical for disease progression both at the hematopoietic stem cell (HSC) and progenitor level (Arranz et al., 2014; Krause et al., 2013; Schepers et al., 2013). However, leukemic stem cell niches might be different in chronic and acute myeloid leukemias. The Scadden
group has demonstrated that activation of osteoblastic cells by parathyroid hormone attenuates chronic myelogenous leukemia (CML), but enhances instead MLL-AF9 oncogene-induced acute myeloid leukemia (Krause et al., 2013). Using a JAK2V617F murine model, we have recently shown that nestin+ mesenchymal stem cells (MSCs) play a pivotal role in regulating the proliferation of mutant MPN HSCs. IL-1b secreted by mutant HSCs induces neural damage to the niche, leading to a marked reduction in nestin+ MSCs, uncontrolled mutant HSC proliferation, and subsequent disease progression (Arranz et al., 2014). Bone marrow stromal cells have been proposed to secrete factors that protect JAK2V617F cells from JAK2 inhibitors (Manshouri et al., 2011). Additionally, the
Passegue´ group has recently demonstrated that CML cells induce expansion of osteoblastic precursors that poorly support normal hematopoietic progenitors (Schepers et al., 2013). CML is an MPN that originates in a mutated hematopoietic stem/progenitor cell (HSPC) carrying the t(9;22)(q34;q11) translocation. This mutation leads to the expression of the BCR/ABL fusion protein, a constitutively active tyrosine kinase that promotes the growth of mutated HSCs and their progeny. In humans, CML presents first with a chronic phase in which differentiated myeloid cells accumulate. This is followed by a short accelerated phase that precedes a rapid blast phase when symptoms aggravate as myeloid cells fail to mature and fully differentiate (Savona and Talpaz, 2008).
Cancer Cell 27, May 11, 2015 ª2015 Elsevier Inc. 611
Cancer Cell
Previews
Figure 1. Model of Manifestation and Progression of Myeloproliferative Neoplasms (1) Myeloproliferative neoplasm (MPN) is originated by a mutated hematopoietic stem cell (Leuk HSC) with increased survival and proliferative capacity. Mutated HSCs secrete IL-1b, which causes damage on sympathetic nervous system (SNS) nerve terminals and MSC apoptosis. (2) Deficiently controlled by the niche, Leuk HSCs generate more mutated leukemic progenitors (Leuk prog) and myeloid cells. (3) Leukemic cells produce IL-6, which transforms normal leukemia-exposed progenitor cells into ‘‘leukemic-like’’ cells, boosting the proliferation of myeloid cells at the expense of lymphocytes. (4) Both Leuk prog and leukemia-exposed progenitors secrete inflammatory cytokines that stimulate disease progression. Osteoblastic cells (OBs) proliferate and become less supportive for normal hematopoietic progenitors.
During the chronic phase of CML, the accumulation of leukemic cells in the bone marrow impairs normal hematopoiesis. HSPCs progressively leave the bone marrow and infiltrate the spleen. If not successfully managed, the reduced number of fully mature, functional blood and immune cells can cause anemias, bleedings, or infections. The displacement of normal hematopoiesis was previously thought to be the passive result of the rapid expansion of leukemic cells in the bone marrow cavity (Savona and Talpaz, 2008). However, the idea of mere movement of normal cells due to outgrowth of leukemic cells is not supported by extramedullary hematopoiesis occurring also with low tumor burden. Alternatively, leukemic cells can modify their niches and outcompete normal HSPCs (Arranz et al., 2014; Colmone et al., 2008; Krause et al., 2013; Schepers et al., 2013; Zhang et al., 2012).
In this issue of Cancer Cell, Welner et al. (2015) propose an alternative explanation for this long-standing question. They show that leukemic cells can directly transform non-mutated HPSCs into functional ‘‘leukemic-like’’ progenitor cells. Welner et al. (2015) used the Scl/Tal1tTA x TRE-BCR/ABL double transgenic mouse model of inducible CML (upon tetracycline removal), previously utilized by this and other groups. To study the interaction between mutated and nonmutated hematopoietic cells—a novel aspect that is also more similar to the human disease—the authors transplanted wild-type hematopoietic cells expressing the CD45.1 isotype together with either SCL-tTA x BCR-ABL CD45.2 leukemic cells or wild-type CD45.2 control cells into lethally irradiated CD45.1 mice. Following transplantation, mice were administered tetracycline for 16 weeks
612 Cancer Cell 27, May 11, 2015 ª2015 Elsevier Inc.
to establish hematopoietic homeostasis and then CML was induced by tetracycline removal. Taking advantage of these chimeric mice, the authors could study the interaction between mutated and non-mutated ‘‘leukemic-exposed’’ cells. Surprisingly, non-mutated cells exposed to leukemic cells adopted some of their features, such as the excessive production of myeloid cells and the deficient generation of lymphoid cells. To understand the cause of this bias in myeloid/lymphoid lineage differentiation, the authors analyzed hematopoietic progenitors—defined as cells expressing the antigens c-kit (at high levels) and sca-1 but lacking expression of lineage markers expressed in mature hematopoietic cells (KSL)—short-term (ST)-HSCs (CD34+ Flt3 KSL cells), and long-term (LT)-HSCs (CD150+ CD48 KSL cells). Interestingly, leukemic-exposed progenitors or ST-HSCs, but not the leukemic-exposed HSCs, showed increased proliferation and accumulation. Subsequent experiments confirmed a clear progenitor bias toward production of myeloid cells at the expense of lymphoid lineages, resembling the mutated leukemic progenitors. However, that was not the case for HSCs, which showed instead impaired self-renewal and reduced capacity to reconstitute the hematopoietic system of transplanted secondary recipients. To investigate the mechanisms leading to these functional modifications, the researchers performed genome-wide gene profiling of purified control or leukemicexposed HSPCs. Interestingly, Gene Set Enrichment Analysis (GSEA) showed a BCR-ABL+ signature in leukemic-exposed progenitors that closely resembled that of mutated leukemic cells. Additionally, the transcriptome of leukemicexposed HSCs was consistent with deficient self-renewal and bone marrow engraftment. But how can leukemic cells make normal cells act alike? It was previously shown that CML generates an inflammatory environment (Reynaud et al., 2011; Kleppe et al., 2015). Welner et al. (2015) confirmed the increased production of the pro-inflammatory cytokines GM-CSF, IL-6, and IL-1a in the chimeric mice. Based on the known functions of each cytokine, the authors focused their attention on IL-6, which had been previously shown to modify
Cancer Cell
Previews leukemic cells (Reynaud et al., 2011). Could this cytokine also transform the function of the normal HSPCs? Consistent with the different effects of the leukemic cells on normal HSCs and progenitors, expression of the IL-6 receptor was found to be much higher in the latter. The authors went on to perform loss-of-function experiments using IL-6 blocking antibodies and an inducible Mx1-Cre;IL-6Raflox/flox system. Both the pharmacological blockade and genetic deletion experiments showed a complete yet transient phenotypic reversion in leukemic-exposed hematopoietic progenitors. Reduced IL-6 production and rescue of the induced leukemiclike phenotypes were also observed in chimeric mice treated with imatinib, the tyrosine-kinase inhibitor currently used to treat CML patients. To address the relevance to human disease, Welner et al. (2015) cultured adult bone marrow CD34+ cells mixed with bone marrow from either healthy subjects or CML patients, obtaining similar results as in the mouse model, i.e., increased IL-6 content and CD34+ cell proliferation, but decreased lymphoid production. These phenotypes were also reverted by IL-6 inhibition. A recent study has shown that both the mutated and non-mutated leukemicexposed hematopoietic cells produce inflammatory cytokines in MPN (Kleppe et al., 2015). This study found IL-6 to be
mainly secreted by the mutated cells. Although the mutations explored in the Welner et al. (2015) study and the Kleppe et al. (2015) study are different, parallels from both studies point toward a scenario in which IL-6 secretion by mutant cells transforms normal hematopoietic cells into leukemic-like cells. In summary, several alterations of normal bone marrow cells induced by mutated HSPCs are required for the manifestation and progression of MPN (Figure 1): (1) neuroglial damage in the bone marrow and induced apoptosis of HSC-niche forming nestin+ MSC, leading to uncontrolled proliferation of mutated HSCs (Arranz et al., 2014); (2) production of pro-inflammatory cytokines by leukemic and normal cells (Reynaud et al., 2011; Kleppe et al., 2015); (3) induction of some leukemic-like features in the normal hematopoietic progenitors (Welner et al., 2015); and (4) excessive proliferation of osteoblastic precursors that become less supportive for hematopoietic progenitors (Krause et al., 2013; Schepers et al., 2013). Targeting the non-mutated bone marrow cells therefore opens up an attractive door for the development of new therapeutic strategies. REFERENCES Arranz, L., Sa´nchez-Aguilera, A., Martı´n-Pe´rez, D., Isern, J., Langa, X., Tzankov, A., Lundberg, P.,
Muntio´n, S., Tzeng, Y.S., Lai, D.M., et al. (2014). Nature 512, 78–81. Colmone, A., Amorim, M., Pontier, A.L., Wang, S., Jablonski, E., and Sipkins, D.A. (2008). Science 322, 1861–1865. Kleppe, M., Kwak, M., Koppikar, P., Riester, M., Keller, M., Bastian, L., Hricik, T., Bhagwat, N., McKenney, A.S., Papalexi, E., et al. (2015). Cancer Discov 5, 316–331. Krause, D.S., Fulzele, K., Catic, A., Sun, C.C., Dombkowski, D., Hurley, M.P., Lezeau, S., Attar, E., Wu, J.Y., Lin, H.Y., et al. (2013). Nat. Med. 19, 1513–1517. Manshouri, T., Estrov, Z., Quinta´s-Cardama, A., Burger, J., Zhang, Y., Livun, A., Knez, L., Harris, D., Creighton, C.J., Kantarjian, H.M., and Verstovsek, S. (2011). Cancer Res. 71, 3831–3840. Reynaud, D., Pietras, E., Barry-Holson, K., Mir, A., Binnewies, M., Jeanne, M., Sala-Torra, O., Radich, J.P., and Passegue´, E. (2011). Cancer Cell 20, 661–673. Savona, M., and Talpaz, M. (2008). Nat. Rev. Cancer 8, 341–350. Schepers, K., Pietras, E.M., Reynaud, D., Flach, J., Binnewies, M., Garg, T., Wagers, A.J., Hsiao, E.C., and Passegue´, E. (2013). Cell Stem Cell 13, 285–299. Welner, R.S., Amabile, G., Bararia, D., Czibere, A., Yang, H., Zhang, H., De Figuereido-Pontes, L.L., Ye, M., Levantini, E., Di Ruscio, A., et al. (2015). Cancer Cell 27, this issue, 671–681. Zhang, B., Ho, Y.W., Huang, Q., Maeda, T., Lin, A., Lee, S.U., Hair, A., Holyoake, T.L., Huettner, C., and Bhatia, R. (2012). Cancer Cell 21, 577–592.
Defining the Molecular Landscape of Ependymomas Tenley C. Archer1,2 and Scott L. Pomeroy1,2,* 1Department
of Neurology, Boston Children’s Hospital, Harvard Medical School Institute of MIT and Harvard Harvard University, Cambridge, MA 02138, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2015.04.015 2Broad
Ependymomas have a variable prognosis. In this issue of Cancer Cell, Pajtler and colleagues identify nine subgroups of ependymoma using DNA methylation profiles. Two subgroups, predominately pediatric, are responsible for most of the mortality, with all others having nearly 100% overall survival after 5 years. For the past several decades, there has been little progress in the treatment of ependymomas. Currently, treatment is
largely restricted to maximal surgical resection and, in some cases, external beam radiation. The tumors do not con-
sistently respond to chemotherapy, and clinical behavior is not accurately predicted by histologic grade. Current
Cancer Cell 27, May 11, 2015 ª2015 Elsevier Inc. 613
