Juvenile Myelomonocytic Leukemia (JMML)
The genomic landscape of JMML is characterized by mutations in one of five genes of the Ras pathway: NF1, NRAS, KRAS, PTPN11, and CBL.[333,334] In a series of 118 consecutively diagnosed JMML cases with Ras pathway–activating mutations, PTPN11 was the most commonly mutated gene, accounting for 51% of cases (19% germline and 32% somatic) (refer to Figure 5).[333] Patients with mutated NRAS accounted for 19% of cases, and patients with mutated KRAS accounted for 15% of cases. NF1 mutations accounted for 8% of cases and CBL mutations accounted for 11% of cases. Although mutations among these five genes are generally mutually exclusive, 10% to 17% of cases have mutations in two of these Ras pathway genes,[333,334] a finding that is associated with poorer prognosis.[333]
The mutation rate in JMML leukemia cells is very low, but additional mutations beyond those of the five Ras pathway genes described above are observed.[333,334] Secondary genomic alterations are observed for genes of the transcriptional repressor complex PRC2 (e.g., ASXL1 was mutated in 7%–8% of cases). Some genes associated with myeloproliferative neoplasms in adults are also mutated at low rates in JMML (e.g., SETBP1was mutated in 7%–9% of cases).[333-335] JAK3 mutations are also observed in a small percentage (4%–12%) of JMML cases.[333-335] Cases with germline PTPN11 and germline CBL mutations showed low rates of additional mutations (refer to Figure 5).[333]
![Chart showing alteration profiles in individual JMML cases. Chart showing alteration profiles in individual JMML cases.](https://www.cancer.gov/images/cdr/live/CDR778293-750.jpg)
General characteristics of leukemia cells provide both prognostic information and guidance regarding therapeutic opportunities for JMML:
- Number of non-RAS pathway mutations. A strong predictor of prognosis for children with JMML is the number of mutations beyond the disease-defining RAS-pathway mutations.[333,334] Of 64 patients (65.3%) at diagnosis, zero or one somatic alteration (pathogenic mutation or monosomy 7) was identified, whereas two or more alterations were identified in 34 (34.7%) patients.[334] In multivariate analysis, mutation number (two or more vs. zero or one) maintained significance as a predictor of inferior event-free survival and overall survival. A higher proportion of patients diagnosed with two or more alterations were older and male, and these patients also demonstrated a higher rate of monosomy 7 or somatic NF1 mutation.[334] Similar findings and observations reported that patients with RAS-pathway double mutations (15 of 96 patients) were at the highest risk of treatment failure.[333]
- RAS-MAPK pathway inhibitors. Because JMML is a disease defined by mutations in the RAS-MAPK pathway, one might speculate that inhibitors of this pathway (e.g., MEK inhibitors) may have clinical utility in the treatment of JMML. However, preclinical data to support this hypothesis are inconsistent,[336,337] and there are no clinical data available.
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- Noguera NI, Breccia M, Divona M, et al.: Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 16 (11): 2185-9, 2002. [PUBMED Abstract]
- Gale RE, Hills R, Pizzey AR, et al.: Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 106 (12): 3768-76, 2005. [PUBMED Abstract]
- Abu-Duhier FM, Goodeve AC, Wilson GA, et al.: Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol 113 (4): 983-8, 2001. [PUBMED Abstract]
- Kutny MA, Moser BK, Laumann K, et al.: FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (4): 662-7, 2012. [PUBMED Abstract]
- Tallman MS, Kim HT, Montesinos P, et al.: Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group. Blood 116 (25): 5650-9, 2010. [PUBMED Abstract]
- Sung L, Aplenc R, Alonzo TA, et al.: Predictors and short-term outcomes of hyperleukocytosis in children with acute myeloid leukemia: a report from the Children's Oncology Group. Haematologica 97 (11): 1770-3, 2012. [PUBMED Abstract]
- Callens C, Chevret S, Cayuela JM, et al.: Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia 19 (7): 1153-60, 2005. [PUBMED Abstract]
- Schnittger S, Bacher U, Haferlach C, et al.: Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA. Haematologica 96 (12): 1799-807, 2011. [PUBMED Abstract]
- Breccia M, Loglisci G, Loglisci MG, et al.: FLT3-ITD confers poor prognosis in patients with acute promyelocytic leukemia treated with AIDA protocols: long-term follow-up analysis. Haematologica 98 (12): e161-3, 2013. [PUBMED Abstract]
- Poiré X, Moser BK, Gallagher RE, et al.: Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype. Leuk Lymphoma 55 (7): 1523-32, 2014. [PUBMED Abstract]
- Pui CH, Relling MV, Rivera GK, et al.: Epipodophyllotoxin-related acute myeloid leukemia: a study of 35 cases. Leukemia 9 (12): 1990-6, 1995. [PUBMED Abstract]
- Inaba H, Zhou Y, Abla O, et al.: Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study. Blood 126 (13): 1575-84, 2015. [PUBMED Abstract]
- Balgobind BV, Raimondi SC, Harbott J, et al.: Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood 114 (12): 2489-96, 2009. [PUBMED Abstract]
- Swansbury GJ, Slater R, Bain BJ, et al.: Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants. Leukemia 12 (5): 792-800, 1998. [PUBMED Abstract]
- Rubnitz JE, Raimondi SC, Tong X, et al.: Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J Clin Oncol 20 (9): 2302-9, 2002. [PUBMED Abstract]
- Mrózek K, Heinonen K, Lawrence D, et al.: Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a Cancer and Leukemia Group B study. Blood 90 (11): 4532-8, 1997. [PUBMED Abstract]
- Martinez-Climent JA, Espinosa R 3rd, Thirman MJ, et al.: Abnormalities of chromosome band 11q23 and the MLL gene in pediatric myelomonocytic and monoblastic leukemias. Identification of the t(9;11) as an indicator of long survival. J Pediatr Hematol Oncol 17 (4): 277-83, 1995. [PUBMED Abstract]
- Casillas JN, Woods WG, Hunger SP, et al.: Prognostic implications of t(10;11) translocations in childhood acute myelogenous leukemia: a report from the Children's Cancer Group. J Pediatr Hematol Oncol 25 (8): 594-600, 2003. [PUBMED Abstract]
- Morerio C, Rosanda C, Rapella A, et al.: Is t(10;11)(p11.2;q23) involving MLL and ABI-1 genes associated with congenital acute monocytic leukemia? Cancer Genet Cytogenet 139 (1): 57-9, 2002. [PUBMED Abstract]
- Taki T, Shibuya N, Taniwaki M, et al.: ABI-1, a human homolog to mouse Abl-interactor 1, fuses the MLL gene in acute myeloid leukemia with t(10;11)(p11.2;q23). Blood 92 (4): 1125-30, 1998. [PUBMED Abstract]
- Coenen EA, Raimondi SC, Harbott J, et al.: Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients: results of an international study. Blood 117 (26): 7102-11, 2011. [PUBMED Abstract]
- Ageberg M, Drott K, Olofsson T, et al.: Identification of a novel and myeloid specific role of the leukemia-associated fusion protein DEK-NUP214 leading to increased protein synthesis. Genes Chromosomes Cancer 47 (4): 276-87, 2008. [PUBMED Abstract]
- Shiba N, Ichikawa H, Taki T, et al.: NUP98-NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia. Genes Chromosomes Cancer 52 (7): 683-93, 2013. [PUBMED Abstract]
- Slovak ML, Gundacker H, Bloomfield CD, et al.: A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare 'poor prognosis' myeloid malignancies. Leukemia 20 (7): 1295-7, 2006. [PUBMED Abstract]
- Alsabeh R, Brynes RK, Slovak ML, et al.: Acute myeloid leukemia with t(6;9) (p23;q34): association with myelodysplasia, basophilia, and initial CD34 negative immunophenotype. Am J Clin Pathol 107 (4): 430-7, 1997. [PUBMED Abstract]
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- Tarlock K, Alonzo TA, Moraleda PP, et al.: Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is associated with poor outcome in childhood AML regardless of FLT3-ITD status: a report from the Children's Oncology Group. Br J Haematol 166 (2): 254-9, 2014. [PUBMED Abstract]
- Gruber TA, Larson Gedman A, Zhang J, et al.: An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell 22 (5): 683-97, 2012. [PUBMED Abstract]
- Thiollier C, Lopez CK, Gerby B, et al.: Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models. J Exp Med 209 (11): 2017-31, 2012. [PUBMED Abstract]
- de Rooij JD, Hollink IH, Arentsen-Peters ST, et al.: NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern. Leukemia 27 (12): 2280-8, 2013. [PUBMED Abstract]
- Masetti R, Pigazzi M, Togni M, et al.: CBFA2T3-GLIS2 fusion transcript is a novel common feature in pediatric, cytogenetically normal AML, not restricted to FAB M7 subtype. Blood 121 (17): 3469-72, 2013. [PUBMED Abstract]
- Masetti R, Rondelli R, Fagioli F, et al.: Infants with acute myeloid leukemia treated according to the Associazione Italiana di Ematologia e Oncologia Pediatrica 2002/01 protocol have an outcome comparable to that of older children. Haematologica 99 (8): e127-9, 2014. [PUBMED Abstract]
- de Rooij JD, Masetti R, van den Heuvel-Eibrink MM, et al.: Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study. Blood 127 (26): 3424-30, 2016. [PUBMED Abstract]
- Hara Y, Shiba N, Ohki K, et al.: Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome. Genes Chromosomes Cancer 56 (5): 394-404, 2017. [PUBMED Abstract]
- Carroll A, Civin C, Schneider N, et al.: The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a Pediatric Oncology Group Study. Blood 78 (3): 748-52, 1991. [PUBMED Abstract]
- Lion T, Haas OA: Acute megakaryocytic leukemia with the t(1;22)(p13;q13). Leuk Lymphoma 11 (1-2): 15-20, 1993. [PUBMED Abstract]
- Duchayne E, Fenneteau O, Pages MP, et al.: Acute megakaryoblastic leukaemia: a national clinical and biological study of 53 adult and childhood cases by the Groupe Français d'Hématologie Cellulaire (GFHC). Leuk Lymphoma 44 (1): 49-58, 2003. [PUBMED Abstract]
- Ma Z, Morris SW, Valentine V, et al.: Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28 (3): 220-1, 2001. [PUBMED Abstract]
- Mercher T, Coniat MB, Monni R, et al.: Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia. Proc Natl Acad Sci U S A 98 (10): 5776-9, 2001. [PUBMED Abstract]
- Bernstein J, Dastugue N, Haas OA, et al.: Nineteen cases of the t(1;22)(p13;q13) acute megakaryblastic leukaemia of infants/children and a review of 39 cases: report from a t(1;22) study group. Leukemia 14 (1): 216-8, 2000. [PUBMED Abstract]
- Coenen EA, Zwaan CM, Reinhardt D, et al.: Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin-Frankfurt-Munster AML-study group. Blood 122 (15): 2704-13, 2013. [PUBMED Abstract]
- Wong KF, Yuen HL, Siu LL, et al.: t(8;16)(p11;p13) predisposes to a transient but potentially recurring neonatal leukemia. Hum Pathol 39 (11): 1702-7, 2008. [PUBMED Abstract]
- Wu X, Sulavik D, Roulston D, et al.: Spontaneous remission of congenital acute myeloid leukemia with t(8;16)(p11;13). Pediatr Blood Cancer 56 (2): 331-2, 2011. [PUBMED Abstract]
- Terui K, Sato T, Sasaki S, et al.: Two novel variants of MOZ-CBP fusion transcripts in spontaneously remitted infant leukemia with t(1;16;8)(p13;p13;p11), a new variant of t(8;16)(p11;p13). Haematologica 93 (10): 1591-3, 2008. [PUBMED Abstract]
- Sainati L, Bolcato S, Cocito MG, et al.: Transient acute monoblastic leukemia with reciprocal (8;16)(p11;p13) translocation. Pediatr Hematol Oncol 13 (2): 151-7, 1996 Mar-Apr. [PUBMED Abstract]
- Weintraub M, Kaplinsky C, Amariglio N, et al.: Spontaneous regression of congenital leukaemia with an 8;16 translocation. Br J Haematol 111 (2): 641-3, 2000. [PUBMED Abstract]
- Classen CF, Behnisch W, Reinhardt D, et al.: Spontaneous complete and sustained remission of a rearrangement CBP (16p13)-positive disseminated congenital myelosarcoma. Ann Hematol 84 (4): 274-5, 2005. [PUBMED Abstract]
- Beverloo HB, Panagopoulos I, Isaksson M, et al.: Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13). Cancer Res 61 (14): 5374-7, 2001. [PUBMED Abstract]
- Slater RM, von Drunen E, Kroes WG, et al.: t(7;12)(q36;p13) and t(7;12)(q32;p13)--translocations involving ETV6 in children 18 months of age or younger with myeloid disorders. Leukemia 15 (6): 915-20, 2001. [PUBMED Abstract]
- von Bergh AR, van Drunen E, van Wering ER, et al.: High incidence of t(7;12)(q36;p13) in infant AML but not in infant ALL, with a dismal outcome and ectopic expression of HLXB9. Genes Chromosomes Cancer 45 (8): 731-9, 2006. [PUBMED Abstract]
- Tosi S, Harbott J, Teigler-Schlegel A, et al.: t(7;12)(q36;p13), a new recurrent translocation involving ETV6 in infant leukemia. Genes Chromosomes Cancer 29 (4): 325-32, 2000. [PUBMED Abstract]
- Park J, Kim M, Lim J, et al.: Three-way complex translocations in infant acute myeloid leukemia with t(7;12)(q36;p13): the incidence and correlation of a HLXB9 overexpression. Cancer Genet Cytogenet 191 (2): 102-5, 2009. [PUBMED Abstract]
- Takeda A, Yaseen NR: Nucleoporins and nucleocytoplasmic transport in hematologic malignancies. Semin Cancer Biol 27: 3-10, 2014. [PUBMED Abstract]
- Brown J, Jawad M, Twigg SR, et al.: A cryptic t(5;11)(q35;p15.5) in 2 children with acute myeloid leukemia with apparently normal karyotypes, identified by a multiplex fluorescence in situ hybridization telomere assay. Blood 99 (7): 2526-31, 2002. [PUBMED Abstract]
- Panarello C, Rosanda C, Morerio C: Cryptic translocation t(5;11)(q35;p15.5) with involvement of the NSD1 and NUP98 genes without 5q deletion in childhood acute myeloid leukemia. Genes Chromosomes Cancer 35 (3): 277-81, 2002. [PUBMED Abstract]
- Cerveira N, Correia C, Dória S, et al.: Frequency of NUP98-NSD1 fusion transcript in childhood acute myeloid leukaemia. Leukemia 17 (11): 2244-7, 2003. [PUBMED Abstract]
- Jaju RJ, Fidler C, Haas OA, et al.: A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood 98 (4): 1264-7, 2001. [PUBMED Abstract]
- Radich JP, Kopecky KJ, Willman CL, et al.: N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 76 (4): 801-7, 1990. [PUBMED Abstract]
- Farr C, Gill R, Katz F, et al.: Analysis of ras gene mutations in childhood myeloid leukaemia. Br J Haematol 77 (3): 323-7, 1991. [PUBMED Abstract]
- Berman JN, Gerbing RB, Alonzo TA, et al.: Prevalence and clinical implications of NRAS mutations in childhood AML: a report from the Children's Oncology Group. Leukemia 25 (6): 1039-42, 2011. [PUBMED Abstract]
- Schnittger S, Kohl TM, Haferlach T, et al.: KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 107 (5): 1791-9, 2006. [PUBMED Abstract]
- Tokumasu M, Murata C, Shimada A, et al.: Adverse prognostic impact of KIT mutations in childhood CBF-AML: the results of the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial. Leukemia 29 (12): 2438-41, 2015. [PUBMED Abstract]
- Cairoli R, Beghini A, Grillo G, et al.: Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood 107 (9): 3463-8, 2006. [PUBMED Abstract]
- Paschka P, Marcucci G, Ruppert AS, et al.: Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol 24 (24): 3904-11, 2006. [PUBMED Abstract]
- Shimada A, Taki T, Tabuchi K, et al.: KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group. Blood 107 (5): 1806-9, 2006. [PUBMED Abstract]
- Shih LY, Liang DC, Huang CF, et al.: Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples. Leukemia 22 (2): 303-7, 2008. [PUBMED Abstract]
- Goemans BF, Zwaan CM, Miller M, et al.: Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia 19 (9): 1536-42, 2005. [PUBMED Abstract]
- Boissel N, Leroy H, Brethon B, et al.: Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia 20 (6): 965-70, 2006. [PUBMED Abstract]
- Pollard JA, Alonzo TA, Gerbing RB, et al.: Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML. Blood 115 (12): 2372-9, 2010. [PUBMED Abstract]
- Paschka P, Marcucci G, Ruppert AS, et al.: Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 26 (28): 4595-602, 2008. [PUBMED Abstract]
- Virappane P, Gale R, Hills R, et al.: Mutation of the Wilms' tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: the United Kingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol 26 (33): 5429-35, 2008. [PUBMED Abstract]
- Gaidzik VI, Schlenk RF, Moschny S, et al.: Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group. Blood 113 (19): 4505-11, 2009. [PUBMED Abstract]
- Renneville A, Boissel N, Zurawski V, et al.: Wilms tumor 1 gene mutations are associated with a higher risk of recurrence in young adults with acute myeloid leukemia: a study from the Acute Leukemia French Association. Cancer 115 (16): 3719-27, 2009. [PUBMED Abstract]
- Ho PA, Zeng R, Alonzo TA, et al.: Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group. Blood 116 (5): 702-10, 2010. [PUBMED Abstract]
- Hollink IH, van den Heuvel-Eibrink MM, Zimmermann M, et al.: Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia. Blood 113 (23): 5951-60, 2009. [PUBMED Abstract]
- Ley TJ, Ding L, Walter MJ, et al.: DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363 (25): 2424-33, 2010. [PUBMED Abstract]
- Yan XJ, Xu J, Gu ZH, et al.: Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 43 (4): 309-15, 2011. [PUBMED Abstract]
- Thol F, Damm F, Lüdeking A, et al.: Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 29 (21): 2889-96, 2011. [PUBMED Abstract]
- Ho PA, Kutny MA, Alonzo TA, et al.: Leukemic mutations in the methylation-associated genes DNMT3A and IDH2 are rare events in pediatric AML: a report from the Children's Oncology Group. Pediatr Blood Cancer 57 (2): 204-9, 2011. [PUBMED Abstract]
- Green CL, Evans CM, Hills RK, et al.: The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status. Blood 116 (15): 2779-82, 2010. [PUBMED Abstract]
- Paschka P, Schlenk RF, Gaidzik VI, et al.: IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol 28 (22): 3636-43, 2010. [PUBMED Abstract]
- Abbas S, Lugthart S, Kavelaars FG, et al.: Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood 116 (12): 2122-6, 2010. [PUBMED Abstract]
- Marcucci G, Maharry K, Wu YZ, et al.: IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 28 (14): 2348-55, 2010. [PUBMED Abstract]
- Wagner K, Damm F, Göhring G, et al.: Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor. J Clin Oncol 28 (14): 2356-64, 2010. [PUBMED Abstract]
- Figueroa ME, Abdel-Wahab O, Lu C, et al.: Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18 (6): 553-67, 2010. [PUBMED Abstract]
- Ward PS, Patel J, Wise DR, et al.: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17 (3): 225-34, 2010. [PUBMED Abstract]
- Dang L, White DW, Gross S, et al.: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462 (7274): 739-44, 2009. [PUBMED Abstract]
- Damm F, Thol F, Hollink I, et al.: Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: a study of the AML-BFM and DCOG study groups. Leukemia 25 (11): 1704-10, 2011. [PUBMED Abstract]
- Oki K, Takita J, Hiwatari M, et al.: IDH1 and IDH2 mutations are rare in pediatric myeloid malignancies. Leukemia 25 (2): 382-4, 2011. [PUBMED Abstract]
- Pigazzi M, Ferrari G, Masetti R, et al.: Low prevalence of IDH1 gene mutation in childhood AML in Italy. Leukemia 25 (1): 173-4, 2011. [PUBMED Abstract]
- Ho PA, Alonzo TA, Kopecky KJ, et al.: Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study. Leukemia 24 (5): 909-13, 2010. [PUBMED Abstract]
- Andersson AK, Miller DW, Lynch JA, et al.: IDH1 and IDH2 mutations in pediatric acute leukemia. Leukemia 25 (10): 1570-7, 2011. [PUBMED Abstract]
- Maxson JE, Ries RE, Wang YC, et al.: CSF3R mutations have a high degree of overlap with CEBPA mutations in pediatric AML. Blood 127 (24): 3094-8, 2016. [PUBMED Abstract]
- Germeshausen M, Kratz CP, Ballmaier M, et al.: RAS and CSF3R mutations in severe congenital neutropenia. Blood 114 (16): 3504-5, 2009. [PUBMED Abstract]
- Skokowa J, Steinemann D, Katsman-Kuipers JE, et al.: Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. Blood 123 (14): 2229-37, 2014. [PUBMED Abstract]
- Caye A, Strullu M, Guidez F, et al.: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet 47 (11): 1334-40, 2015. [PUBMED Abstract]
- Stieglitz E, Taylor-Weiner AN, Chang TY, et al.: The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet 47 (11): 1326-33, 2015. [PUBMED Abstract]
- Sakaguchi H, Okuno Y, Muramatsu H, et al.: Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 45 (8): 937-41, 2013. [PUBMED Abstract]
- Hernández-Porras I, Fabbiano S, Schuhmacher AJ, et al.: K-RasV14I recapitulates Noonan syndrome in mice. Proc Natl Acad Sci U S A 111 (46): 16395-400, 2014. [PUBMED Abstract]
- Chang T, Krisman K, Theobald EH, et al.: Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest 123 (1): 335-9, 2013. [PUBMED Abstract]
Non-Hodgkin Lymphoma
Mature B-cell Lymphoma
The mature B-cell lymphomas include Burkitt and Burkitt-like lymphoma, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma.
Burkitt and Burkitt-like lymphoma
The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin, most bearing a clonal surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD19, CD20, CD22) are usually present, and most childhood Burkitt and Burkitt-like lymphomas/leukemias express CALLA (CD10).[1]
Burkitt lymphoma/leukemia expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the MYConcogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of MYC, a gene involved in cellular proliferation.[2-4] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.[5]
While MYC translocations are present in all Burkitt lymphoma, cooperating genomic alterations appear to be required for lymphoma development. Recurring mutations that have been identified in Burkitt lymphoma in pediatric and adult cases are listed below. The clinical significance of these mutations for pediatric Burkitt lymphoma remains to be elucidated.
- Activating mutations in the transcription factor TCF3 and inactivating mutations in its negative regulator ID3 are observed in approximately 70% of Burkitt lymphoma cases.[6-9]
- Mutations in TP53 are observed in one-third to one-half of cases.[6,8]
- Mutations in cyclin D3 (CCND3) are commonly observed in sporadic Burkitt lymphoma (approximately 40% of cases) but are rare in endemic Burkitt lymphoma.[6,8]
- Mutations in MYC itself are observed in approximately one-half of Burkitt lymphoma cases and appear to increase MYC stability.[6,10]
The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma/leukemia consists of uniform, small, noncleaved cells, whereas the diagnosis of Burkitt-like lymphoma/leukemia is highly disputed among pathologists because of features that are consistent with diffuse large B-cell lymphoma.[11]
Cytogenetic evidence of MYC rearrangement is the gold standard for diagnosis of Burkitt lymphoma/leukemia. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma/leukemia or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater.[1] BCL2 staining by immunohistochemistry is variable. The absence of a translocation involving the BCL2 gene does not preclude the diagnosis of Burkitt lymphoma/leukemia and has no clinical implications.[12]
Studies have demonstrated that the vast majority of Burkitt-like or atypical Burkittlymphoma/leukemia has a gene expression signature similar to Burkitt lymphoma/leukemia.[13,14] Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma/leukemia.[13,15]
(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)
Diffuse large B-cell lymphoma
The World Health Organization (WHO) classification system does not recommend subclassification of diffuse large B-cell lymphoma on the basis of morphologic variants (e.g., immunoblastic, centroblastic).[16]
Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:
- The vast majority of pediatric diffuse large B-cell lymphoma cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10.[5,17,18] The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.[19]
- Pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene that is seen in adults.[17]
- As many as 30% of patients younger than 14 years with diffuse large B-cell lymphoma will have a gene signature similar to Burkitt lymphoma/leukemia.[13,15]
- In contrast to adult diffuse large B-cell lymphoma, pediatric cases show a high frequency of abnormalities at the MYC locus (chromosome 8q24), with approximately one-third of pediatric cases showing MYC rearrangement and with approximately one-half of the nonrearranged cases showing MYC gain or amplification.[15,20]
- A subset of pediatric diffuse large B-cell lymphoma cases was found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci. Diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than in adults (15% vs. 2%), were germinal center–derived B-cell lymphomas, and were associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality.[21] Large B-cell lymphoma with IRF4 rearrangement was added as a distinct entity in the 2016 revision of the WHO classification of lymphoid neoplasms.[22]
(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)
Primary mediastinal B-cell lymphoma
Primary mediastinal B-cell lymphoma was previously considered a subtype of diffuse large B-cell lymphoma, but is now a separate entity in the most recent World Health Organization (WHO) classification.[23] These tumors arise in the mediastinum from thymic B-cells and show a diffuse large cell proliferation with sclerosis that compartmentalizes neoplastic cells.
Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:
- Diffuse large B-cell lymphoma: Cell surface markers are similar to the ones seen in diffuse large B-cell lymphoma, such as CD19, CD20, CD22, CD79a, and PAX-5. Primary mediastinal B-cell lymphoma often lacks cell surface immunoglobulin expression but may display cytoplasmic immunoglobulins. CD30 expression is commonly present.[23]
- Hodgkin lymphoma: Primary mediastinal B-cell lymphoma may be difficult to clinically and morphologically distinguish from Hodgkin lymphoma, especially with small mediastinal biopsies because of extensive sclerosis and necrosis.
Primary mediastinal B-cell lymphoma has a distinctive gene expression profile compared with diffuse large B-cell lymphoma; however, its gene expression profile has features similar to those seen in Hodgkin lymphoma.[24,25] Primary mediastinal B-cell lymphoma is also associated with a distinctive constellation of chromosomal aberrations compared with other NHL subtypes. Because primary mediastinal B-cell lymphoma is primarily a cancer of adolescents and young adults, the genomic findings are presented without regard to age.
- Structural rearrangements and copy number gains at chromosome 9p24 are common in primary mediastinal B-cell lymphoma. This region encodes the immune checkpoint genes PD-L1 (PDL1) and PD-L2 (PDCD1LG2), and the genomic alterations lead to increased expression of these checkpoint proteins.[26-28]
- Genomic alterations in CIITA, which is the master transcriptional regulator of MHC class II expression, are common in primary mediastinal B-cell lymphoma and lead to loss of MHC class II expression. Loss of MHC class II expression provides another mechanism of immune escape for primary mediastinal B-cell lymphoma.[29]
- Genomic alterations involving JAK-STAT pathway genes are observed in most cases of primary mediastinal B-cell lymphoma.[30]
- The chromosome 9p region that shows gains and amplification in primary mediastinal B-cell lymphoma encodes Janus kinase 2 (JAK2), which activates the signal transducer and activator of transcription (STAT) pathway.[31,32]
- SOCS1, a negative regulator of JAK-STAT signaling, is inactivated in approximately 50% of primary mediastinal B-cell lymphoma by either mutation or gene deletion.[33,34]
- The interleukin-4 receptor gene (IL4R) shows activating mutations in approximately 20% of primary mediastinal B-cell lymphoma cases, and IL4R activation leads to increased JAK-STAT pathway activity.[30]
- Copy number gains and amplifications at 2p16.1, a region that encodes BCL11A and REL, also occur in primary mediastinal B-cell lymphoma.[31,32]
(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)
Lymphoblastic Lymphoma
Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.[2,35]
As opposed to pediatric acute lymphoblastic leukemia, chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not well characterized. The Berlin-Frankfurt-Münster group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients and NOTCH1 mutations were seen in 60% of patients, but NOTCH1 mutations are rarely seen in patients with loss of heterozygosity in 6q16.[36,37]
(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)
Anaplastic Large Cell Lymphoma
While the predominant immunophenotype of anaplastic large cell lymphoma is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or natural killer-cell surface antigen expression) does occur. The World Health Organization (WHO) classifies anaplastic large cell lymphoma as a subtype of peripheral T-cell lymphoma.[22]
All anaplastic large cell lymphoma cases are CD30-positive. More than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the fusion protein NPM-ALK; the other 15% of cases are composed of variant ALK translocations.[38] Anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM-ALK fusion protein, whereas cytoplasmic staining only of ALK is associated with the variant ALK translocations, as shown in Table 2.[39]
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