Cancer Cell
Previews W.S., and Hua, X. (2006). Proc. Natl. Acad. Sci. USA 103, 1018–1023. Daigle, S.R., Olhava, E.J., Therkelsen, C.A., Basavapathruni, A., Jin, L., Boriack-Sjodin, P.A., Allain, C.J., Klaus, C.R., Raimondi, A., Scott, M.P., et al. (2013). Blood 122, 1017–1025. Li, B.E., Gan, T., Meyerson, M., Rabbitts, T.H., and Ernst, P. (2013). Blood 122, 2039–2046.
Maillard, I., Chen, Y.X., Friedman, A., Yang, Y., Tubbs, A.T., Shestova, O., Pear, W.S., and Hua, X. (2009). Blood 113, 1661–1669. Meyer, C., Hofmann, J., Burmeister, T., Gro¨ger, D., Park, T.S., Emerenciano, M., Pombo de Oliveira, M., Renneville, A., Villarese, P., Macintyre, E., et al. (2013). Leukemia 27, 2165–2176.
Neff, T., and Armstrong, S.A. (2013). Blood 121, 4847–4853. Yokoyama, A., and Cleary, M.L. (2008). Cancer Cell 14, 36–46. Yokoyama, A., Somervaille, T.C., Smith, K.S., Rozenblatt-Rosen, O., Meyerson, M., and Cleary, M.L. (2005). Cell 123, 207–218.
When One Mutation Is All It Takes Mel Greaves1,* 1Centre for Evolution and Cancer, The Institute of Cancer Research, London, Brookes Lawley Building, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2015.03.016
In a recent issue of Nature Genetics, Andersson and colleagues report that MLL fusion alone may be sufficient to spawn an aggressive leukemia in infants. Some other pediatric cancers may share a similar, single, ‘‘bighit’’ origin, possibly reflecting a critical developmental window of stem cell vulnerability.
Acute leukemias in infants are rare but highly malignant and clinically intransigent (Biondi et al., 2000). The majority of leukemias have phenotypic features of early or pro-B cells and recurrent rearrangements of MLL, predominantly as chimeric gene fusions with AF4 (aka AFF1) (Biondi et al., 2000). Monozygotic twin infant pairs with concordant acute lymphoblastic leukemia (ALL) share an identical but nonconstitutive MLL genomic rearrangement indicative of a single cell in utero origin and progeny cell transfer via intraplacental anastomoses (Greaves et al., 2003). In non-twinned infants with ALL, the MLL genomic sequence is detectable in archived neonatal blood spots, suggesting a pre-natal origin for most patients (Gale et al., 1997). The concordance rate for ALL in identical twin infants with a monochorionic, or single placenta is close to 100%. This, coupled with the very short pre-clinical latency, has suggested that MLL fusion might by itself be sufficient for leukemia (Greaves et al., 2003). Data from whole genome sequencing of three cases of infant ALL with MLL-AF4 fusion were compatible with this notion (Dobbins et al., 2013). In contrast, older children with B cell pre-
cursor driven by ETV6-RUNX1 fusion or hyperdiploidy also have a predominantly in utero origin, but a requirement for additional post-natal mutations and a concordance rate of 15% (Greaves et al., 2003). At face value, this possibility of a single driver mutation conflicts with the conventional notion that multiple and sequential genetic changes need to be accrued for a malignant phenotype to emerge. In a recent publication, Andersson et al. (2015) reported a detailed genomic scrutiny of 22 cases of infant ALL with MLLR (rearrangements). They provided convincing evidence that MLL gene fusion is the only detectable genome-wide abnormality that is present in all the cells. Other mutations are present, particularly in the P13K-RAS signaling pathway, but these are subclonal (allele frequencies < 30%) and not always retained in relapse. Older children with MLL rearranged ALL had more complex mutational landscapes. These data suggest that, although additional ‘‘driver’’ mutations occur in infant ALL, the initiating lesion MLL fusion is probably sufficient in itself to spawn a large malignant clone (patients with MLLR ALL have very high tumor
burdens or white cell counts; Biondi et al., 2000). This important finding is not unique to infant leukemia. In highly malignant pediatric rhabdoid tumors, the only discernible and recurrent exomic genetic aberration is mutation and/or deletion, leading to homozygous loss of function in SMARCB1 (Lee et al., 2012). Paediatric brain ependymomas subtypes are very malignant but have remarkably silent genomic landscapes with only one genetic alteration: C11orf95-RELA fusion found in most supratentorial ependymomas (Parker et al., 2014). Other hindbrain (posterior-fossa, group B) ependymomas have no recurrent single nucleotide variants, but large-scale copy number changes (or aneuploidy) were present along with genome-wide epigenetic (methylation) changes (Mack et al., 2014). It is possible that the sequencing technologies employed in these studies missed some cryptic mutational changes, particularly in non-coding regions. Additionally, germline or constitutive genetic variants may have contributed, epistatistically, to malignant transformation. These caveats aside, the data collectively argue that signal mutations can, exceptionally, have a major impact on cellular
Cancer Cell 27, April 13, 2015 ª2015 Elsevier Inc. 433
Cancer Cell
Previews
Stem cells / progenitors fitness and empower a fully described above have a malignant phenotype. ‘‘big bang’’ or explosive genPaediatric cancers genereration in a short time frame. ally have far fewer mutaHaving cells that can be Developmentally tions than adult epithelial converted to highly maligtimed window: MLL fusions carcinomas (Vogelstein et al., nant derivatives by a single Self-renewal ON Permissive / supportive del SMARCB1 micro-environment 2013), and it is possible that step seems a very dangerous Differentiation OFF two complementary driver liability. The fortunate rarity C11orf95-REL mutations could be sufficient, of these cancers may then in accord with Knudson’s reflect the very low probabiloriginal two-hit hypothesis. ity of those mutations occurBut how is it possible for a ring during a very transient single mutation to spawn a time window and with only Normal Mutant fully-fledged malignant clone small numbers of cells and in such a short time at risk. Stem cell D+ progeny progeny frame? The answer may reside in ACKNOWLEDGMENTS Figure 1. Trapping Stem Cells in a Normally Transient the functional properties of Developmental Window of Expansion the mutant genes that have M.G. is supported by the Wellcome this capacity and their Trust [105104/Z/14/Z], Leukaemia & contextual relation to the developmental upon cell type, genotypic networks, and Lymphoma Research, and the Kay Kendall timing and cellular targets involved. It is epistasis in that cell type and local ecolog- Leukaemia Fund. striking that all three genetic lesions ical or micro-environmental conditions. (MLL fusions, SMARCB1 deletion, and One plausible explanation for these C11orf95-RELA) corrupt regulation of remarkable observations (Figure 1) is REFERENCES cell fate and gene transcription. MLL that there is a developmental window durAndersson, A.K., Ma, J., Wang, J., Chen, X., Gedproteins (and many of their fusion part- ing embryonic or fetal development when man, A.L., Dang, J., Nakitandwe, J., Holmfeldt, L., ners) are global chromatin remodellers stem cells or progenitors are epigeneti- Parker, M., Easton, J., et al.; St. Jude Children’s (Krivtsov and Armstrong, 2007) as is cally plastic and in a very supportive or Research Hospital–Washington University Pediatric Cancer Genome Project (2015). Nat. Genet. SMARCB1, as part of the SWI/SNF com- permissive microenvironment for prolifer- 47, 330–337. plex (Lee et al., 2012). C11orf95-RELA ative expansion. Mutation of cell-fate regBiondi, A., Cimino, G., Pieters, R., and Pui, C.-H. deregulates REL to activate multiple tran- ulators at this critical stage might then (2000). Blood 96, 24–33. scriptional targets of canonial NF-kB trap stem cells or progenitors in a self-resignaling (Parker et al., 2014). MLL fusions newing mode with no exit route of differ- Dobbins, S.E., Sherborne, A.L., Ma, Y.P., Bardini, M., Biondi, A., Cazzaniga, G., Lloyd, A., Chubb, have been reported to deregulate multiple entiation available. A normally very active D., Greaves, M.F., and Houlston, R.S. (2013). kip1 genes including CDKN1B (p27 ), TERT but transitory cell expansion is now fixed Genes Chromosomes Cancer 52, 954–960. subunit of telomerase, TP53 and, in or stabilized. This proposition can be asGale, K.B., Ford, A.M., Repp, R., Borkhardt, A., particular, HOX genes. The latter are sessed with modeling in murine systems Keller, C., Eden, O.B., and Greaves, M.F. (1997). normally downregulated in haemopoietic (Krivtsov and Armstrong, 2007; Parker Proc. Natl. Acad. Sci. USA 94, 13950–13954. differentiation but become fixed in an et al., 2014), though the relevant cell types Greaves, M.F., Maia, A.T., Wiemels, J.L., and Ford, ‘‘on mode’’ in progenitor cells trans- and tissue ecological context might be A.M. (2003). Blood 102, 2321–2333. formed by MLLR, concomitant with the tricky to access. Krivtsov, A.V., and Armstrong, S.A. (2007). Nat. expression of self-renewal or stem cell One prediction is that all cells experi- Rev. Cancer 7, 823–833. signatures (Krivtsov and Armstrong, mentally transformed by these particular Lee, R.S., Stewart, C., Carter, S.L., Ambrogio, L., 2007). The pleiotypic impact of each of mutational changes will have constitutive Cibulskis, K., Sougnez, C., Lawrence, M.S., the three mutant genes may have an stem cell properties, in contrast to the Auclair, D., Mora, J., Golub, T.R., et al. (2012). equivalent phenotypic impact on cellular hierarchical lineage structure generated J. Clin. Invest. 122, 2983–2988. fitness as several independent mutations in most cancers where fusion genes Mack, S.C., Witt, H., Piro, R.M., Gu, L., Zuyderand other initiating genetic lesions (e.g., duyn, S., Stu¨tz, A.M., Wang, X., Gallo, M., Garzia, in other genes. L., Zayne, K., et al. (2014). Nature 506, 445–450. Each of these three types of genetic ab- ETV6-RUNX1 in childhood ALL) provide normalities, or their signaling pathways, is a more subtle fitness advantage. There Parker, M., Mohankumar, K.M., Punchihewa, C., R., Dalton, J.D., Li, Y., Lee, R., Tatevosalso found in adult cancers but in the is some evidence that MLL fusions are Weinlich, sian, R.G., Phoenix, T.N., Thiruvenkatam, R., context of additional driver mutations. potent stem cell converters (Krivtsov et al. (2014). Nature 506, 451–455. There must therefore be something spe- and Armstrong, 2007; Somervaille and Somervaille, T.C., and Cleary, M.L. (2006). Cancer cial about the pediatric context or target Cleary, 2006). A corollary is that, Cell 10, 257–268. cells involved (Andersson et al., 2015; whereas most cancers follow a relatively Vogelstein, B., Papadopoulos, N., Velculescu, Lee et al., 2012). The fitness impact of all protracted and punctuated evolutionary V.E., Zhou, S., Diaz, L.A., Jr., and Kinzler, K.W. mutational drivers in cancer is contingent path, pediatric tumors of the type (2013). Science 339, 1546–1558.
434 Cancer Cell 27, April 13, 2015 ª2015 Elsevier Inc.
Previews W.S., and Hua, X. (2006). Proc. Natl. Acad. Sci. USA 103, 1018–1023. Daigle, S.R., Olhava, E.J., Therkelsen, C.A., Basavapathruni, A., Jin, L., Boriack-Sjodin, P.A., Allain, C.J., Klaus, C.R., Raimondi, A., Scott, M.P., et al. (2013). Blood 122, 1017–1025. Li, B.E., Gan, T., Meyerson, M., Rabbitts, T.H., and Ernst, P. (2013). Blood 122, 2039–2046.
Maillard, I., Chen, Y.X., Friedman, A., Yang, Y., Tubbs, A.T., Shestova, O., Pear, W.S., and Hua, X. (2009). Blood 113, 1661–1669. Meyer, C., Hofmann, J., Burmeister, T., Gro¨ger, D., Park, T.S., Emerenciano, M., Pombo de Oliveira, M., Renneville, A., Villarese, P., Macintyre, E., et al. (2013). Leukemia 27, 2165–2176.
Neff, T., and Armstrong, S.A. (2013). Blood 121, 4847–4853. Yokoyama, A., and Cleary, M.L. (2008). Cancer Cell 14, 36–46. Yokoyama, A., Somervaille, T.C., Smith, K.S., Rozenblatt-Rosen, O., Meyerson, M., and Cleary, M.L. (2005). Cell 123, 207–218.
When One Mutation Is All It Takes Mel Greaves1,* 1Centre for Evolution and Cancer, The Institute of Cancer Research, London, Brookes Lawley Building, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2015.03.016
In a recent issue of Nature Genetics, Andersson and colleagues report that MLL fusion alone may be sufficient to spawn an aggressive leukemia in infants. Some other pediatric cancers may share a similar, single, ‘‘bighit’’ origin, possibly reflecting a critical developmental window of stem cell vulnerability.
Acute leukemias in infants are rare but highly malignant and clinically intransigent (Biondi et al., 2000). The majority of leukemias have phenotypic features of early or pro-B cells and recurrent rearrangements of MLL, predominantly as chimeric gene fusions with AF4 (aka AFF1) (Biondi et al., 2000). Monozygotic twin infant pairs with concordant acute lymphoblastic leukemia (ALL) share an identical but nonconstitutive MLL genomic rearrangement indicative of a single cell in utero origin and progeny cell transfer via intraplacental anastomoses (Greaves et al., 2003). In non-twinned infants with ALL, the MLL genomic sequence is detectable in archived neonatal blood spots, suggesting a pre-natal origin for most patients (Gale et al., 1997). The concordance rate for ALL in identical twin infants with a monochorionic, or single placenta is close to 100%. This, coupled with the very short pre-clinical latency, has suggested that MLL fusion might by itself be sufficient for leukemia (Greaves et al., 2003). Data from whole genome sequencing of three cases of infant ALL with MLL-AF4 fusion were compatible with this notion (Dobbins et al., 2013). In contrast, older children with B cell pre-
cursor driven by ETV6-RUNX1 fusion or hyperdiploidy also have a predominantly in utero origin, but a requirement for additional post-natal mutations and a concordance rate of 15% (Greaves et al., 2003). At face value, this possibility of a single driver mutation conflicts with the conventional notion that multiple and sequential genetic changes need to be accrued for a malignant phenotype to emerge. In a recent publication, Andersson et al. (2015) reported a detailed genomic scrutiny of 22 cases of infant ALL with MLLR (rearrangements). They provided convincing evidence that MLL gene fusion is the only detectable genome-wide abnormality that is present in all the cells. Other mutations are present, particularly in the P13K-RAS signaling pathway, but these are subclonal (allele frequencies < 30%) and not always retained in relapse. Older children with MLL rearranged ALL had more complex mutational landscapes. These data suggest that, although additional ‘‘driver’’ mutations occur in infant ALL, the initiating lesion MLL fusion is probably sufficient in itself to spawn a large malignant clone (patients with MLLR ALL have very high tumor
burdens or white cell counts; Biondi et al., 2000). This important finding is not unique to infant leukemia. In highly malignant pediatric rhabdoid tumors, the only discernible and recurrent exomic genetic aberration is mutation and/or deletion, leading to homozygous loss of function in SMARCB1 (Lee et al., 2012). Paediatric brain ependymomas subtypes are very malignant but have remarkably silent genomic landscapes with only one genetic alteration: C11orf95-RELA fusion found in most supratentorial ependymomas (Parker et al., 2014). Other hindbrain (posterior-fossa, group B) ependymomas have no recurrent single nucleotide variants, but large-scale copy number changes (or aneuploidy) were present along with genome-wide epigenetic (methylation) changes (Mack et al., 2014). It is possible that the sequencing technologies employed in these studies missed some cryptic mutational changes, particularly in non-coding regions. Additionally, germline or constitutive genetic variants may have contributed, epistatistically, to malignant transformation. These caveats aside, the data collectively argue that signal mutations can, exceptionally, have a major impact on cellular
Cancer Cell 27, April 13, 2015 ª2015 Elsevier Inc. 433
Cancer Cell
Previews
Stem cells / progenitors fitness and empower a fully described above have a malignant phenotype. ‘‘big bang’’ or explosive genPaediatric cancers genereration in a short time frame. ally have far fewer mutaHaving cells that can be Developmentally tions than adult epithelial converted to highly maligtimed window: MLL fusions carcinomas (Vogelstein et al., nant derivatives by a single Self-renewal ON Permissive / supportive del SMARCB1 micro-environment 2013), and it is possible that step seems a very dangerous Differentiation OFF two complementary driver liability. The fortunate rarity C11orf95-REL mutations could be sufficient, of these cancers may then in accord with Knudson’s reflect the very low probabiloriginal two-hit hypothesis. ity of those mutations occurBut how is it possible for a ring during a very transient single mutation to spawn a time window and with only Normal Mutant fully-fledged malignant clone small numbers of cells and in such a short time at risk. Stem cell D+ progeny progeny frame? The answer may reside in ACKNOWLEDGMENTS Figure 1. Trapping Stem Cells in a Normally Transient the functional properties of Developmental Window of Expansion the mutant genes that have M.G. is supported by the Wellcome this capacity and their Trust [105104/Z/14/Z], Leukaemia & contextual relation to the developmental upon cell type, genotypic networks, and Lymphoma Research, and the Kay Kendall timing and cellular targets involved. It is epistasis in that cell type and local ecolog- Leukaemia Fund. striking that all three genetic lesions ical or micro-environmental conditions. (MLL fusions, SMARCB1 deletion, and One plausible explanation for these C11orf95-RELA) corrupt regulation of remarkable observations (Figure 1) is REFERENCES cell fate and gene transcription. MLL that there is a developmental window durAndersson, A.K., Ma, J., Wang, J., Chen, X., Gedproteins (and many of their fusion part- ing embryonic or fetal development when man, A.L., Dang, J., Nakitandwe, J., Holmfeldt, L., ners) are global chromatin remodellers stem cells or progenitors are epigeneti- Parker, M., Easton, J., et al.; St. Jude Children’s (Krivtsov and Armstrong, 2007) as is cally plastic and in a very supportive or Research Hospital–Washington University Pediatric Cancer Genome Project (2015). Nat. Genet. SMARCB1, as part of the SWI/SNF com- permissive microenvironment for prolifer- 47, 330–337. plex (Lee et al., 2012). C11orf95-RELA ative expansion. Mutation of cell-fate regBiondi, A., Cimino, G., Pieters, R., and Pui, C.-H. deregulates REL to activate multiple tran- ulators at this critical stage might then (2000). Blood 96, 24–33. scriptional targets of canonial NF-kB trap stem cells or progenitors in a self-resignaling (Parker et al., 2014). MLL fusions newing mode with no exit route of differ- Dobbins, S.E., Sherborne, A.L., Ma, Y.P., Bardini, M., Biondi, A., Cazzaniga, G., Lloyd, A., Chubb, have been reported to deregulate multiple entiation available. A normally very active D., Greaves, M.F., and Houlston, R.S. (2013). kip1 genes including CDKN1B (p27 ), TERT but transitory cell expansion is now fixed Genes Chromosomes Cancer 52, 954–960. subunit of telomerase, TP53 and, in or stabilized. This proposition can be asGale, K.B., Ford, A.M., Repp, R., Borkhardt, A., particular, HOX genes. The latter are sessed with modeling in murine systems Keller, C., Eden, O.B., and Greaves, M.F. (1997). normally downregulated in haemopoietic (Krivtsov and Armstrong, 2007; Parker Proc. Natl. Acad. Sci. USA 94, 13950–13954. differentiation but become fixed in an et al., 2014), though the relevant cell types Greaves, M.F., Maia, A.T., Wiemels, J.L., and Ford, ‘‘on mode’’ in progenitor cells trans- and tissue ecological context might be A.M. (2003). Blood 102, 2321–2333. formed by MLLR, concomitant with the tricky to access. Krivtsov, A.V., and Armstrong, S.A. (2007). Nat. expression of self-renewal or stem cell One prediction is that all cells experi- Rev. Cancer 7, 823–833. signatures (Krivtsov and Armstrong, mentally transformed by these particular Lee, R.S., Stewart, C., Carter, S.L., Ambrogio, L., 2007). The pleiotypic impact of each of mutational changes will have constitutive Cibulskis, K., Sougnez, C., Lawrence, M.S., the three mutant genes may have an stem cell properties, in contrast to the Auclair, D., Mora, J., Golub, T.R., et al. (2012). equivalent phenotypic impact on cellular hierarchical lineage structure generated J. Clin. Invest. 122, 2983–2988. fitness as several independent mutations in most cancers where fusion genes Mack, S.C., Witt, H., Piro, R.M., Gu, L., Zuyderand other initiating genetic lesions (e.g., duyn, S., Stu¨tz, A.M., Wang, X., Gallo, M., Garzia, in other genes. L., Zayne, K., et al. (2014). Nature 506, 445–450. Each of these three types of genetic ab- ETV6-RUNX1 in childhood ALL) provide normalities, or their signaling pathways, is a more subtle fitness advantage. There Parker, M., Mohankumar, K.M., Punchihewa, C., R., Dalton, J.D., Li, Y., Lee, R., Tatevosalso found in adult cancers but in the is some evidence that MLL fusions are Weinlich, sian, R.G., Phoenix, T.N., Thiruvenkatam, R., context of additional driver mutations. potent stem cell converters (Krivtsov et al. (2014). Nature 506, 451–455. There must therefore be something spe- and Armstrong, 2007; Somervaille and Somervaille, T.C., and Cleary, M.L. (2006). Cancer cial about the pediatric context or target Cleary, 2006). A corollary is that, Cell 10, 257–268. cells involved (Andersson et al., 2015; whereas most cancers follow a relatively Vogelstein, B., Papadopoulos, N., Velculescu, Lee et al., 2012). The fitness impact of all protracted and punctuated evolutionary V.E., Zhou, S., Diaz, L.A., Jr., and Kinzler, K.W. mutational drivers in cancer is contingent path, pediatric tumors of the type (2013). Science 339, 1546–1558.
434 Cancer Cell 27, April 13, 2015 ª2015 Elsevier Inc.
