Acute lymphoblastic leukemia (ALL) in infants (< 1 year) is characterized by a poor prognosis and a high incidence of MLL translocations. Several studies demonstrated the unique gene expression profile associated with MLL-rearranged ALL, but generally small cohorts were analyzed as uniform patient groups regardless of the type of MLL translocation, whereas the analysis of translocationnegative infant ALL remained unacknowledged. Here we generated and analyzed primary infant ALL expression profiles (n ‫؍‬ 73) typified by translocations t(4;11), t(11;19), and t(9;11), or the absence of MLL translocations. Our data show that MLL germline infant ALL specifies a gene expression pattern that is different from both MLL-rearranged infant ALL and pediatric precursor B-ALL. Moreover, we demonstrate that, apart from a fundamental signature shared by all MLL-rearranged infant ALL samples, each type of MLL translocation is associated with a translocation-specific gene expression signature. Finally, we show the existence of

Acute lymphoblastic leukemia (ALL) diagnosed in the first month of life (congenital ALL) is very rare. Although congenital ALL is often assumed to be fatal, no studies have been published on outcome except for case reports. The present study reports the outcome of 30 patients with congenital ALL treated with the uniform Interfant-99 protocol, a hybrid regimen combining ALL treatment with elements designed for treatment of acute myeloid leukemia. Congenital ALL was characterized by a higher white blood cell count and a strong trend for higher incidence of MLL rearrangements and CD10-negative B-lineage ALL compared with older infants. Induction failure rate was 13% and not significantly different from that in older infants (7%, P ‫؍‬ .14), but relapse rate was significantly higher in congenital ALL patients (2-year cumulative incidence [ IntroductionAcute lymphoblastic leukemia (ALL) in infants (up to 1 year of age) is known to be biologically different from ALL in older children diagnosed with ALL. ALL in infants is more often associated with a higher tumor load at diagnosis, 1,2 a rearrangement in the mixed lineage leukemia (MLL) gene, and very immature B-cell phenotype (pro-B ALL) without CD10 expression. 1-3 Infant ALL cells are more resistant to several standard chemotherapeutic agents, 3,4 and the disease is also characterized by a poorer prognosis compared with older children. [5][6][7][8][9][10][11][12][13][14] Congenital ALL is diagnosed at birth or within the first month of life and is very rare. Although it is assumed to be inevitably fatal and the toxicity of the chemotherapeutic agents in these very young infants is unclear, to the best of our knowledge, no series have been published on congenital ALL except for case reports. Bresters et al 15 reviewed 24 patients with congenital ALL diagnosed over 25 years who were described in case reports: all patients died.We recently reported the results of a large international collaborative trial, Interfant-99, in infants younger than 1 year with ALL. 14 Here, we detail the outcome and characteristics of 30 patients with congenital ALL who received uniform therapy with curative intent. Methods PatientsThe Interfant-99 trial design, the inclusion criteria, and recruitment methods have been published earlier. 14 Individual study groups obtained ethics approval from all participating institutions, and patient informed consent was obtained in accordance with the Declaration of Helsinki. Of the 518 infants diagnosed with ALL, which account for approximately 3% of the ALL population, 35 patients were younger than 1 month, confirming the rarity of congenital ALL (ϳ 2 children per every 1000 with ALL). The present study reports on 30 cases that were treated with Interfant-99 (Figure 1). ProceduresEnrolled patients were stratified into standard-risk and high-risk groups on the basis of their response to 1 week of daily systemic prednisone (at a dose of 60 mg/m 2 ) and 1 intrathecal dose of methotrexate. Patients were classified as standard risk if their peripheral bloo...

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Acute lymphoblastic leukemia in infants (< 1 year-of-age) is characterized by a high incidence of MLL rearrangements. Recently, direct targets of the MLL fusion protein have been identified. However, functional validation of the identified targets remained unacknowledged. In this study, we identify CDK6 as a direct target of the MLL fusion protein and an important player in the proliferation advantage of MLL-rearranged leukemia. CDK6 mRNA was significantly higher expressed in MLL-rearranged infant ALL patients compared with MLL wild-type ALL patients (P < 0.001). Decrease of MLL-AF4 and MLL-ENL fusion mRNA expression by siRNAs resulted in downregulation of CDK6, affirming a direct relationship between the presence of the MLL fusion and CDK6 expression. Knockdown of CDK6 itself significantly inhibited proliferation in the MLL-AF4-positive cell line SEM, whereas knockdown of the highly homologous gene CDK4 had virtually no effect on the cell cycle. Furthermore, we show in vitro sensitivity of MLL-rearranged leukemia cell lines to the CDK4/6-inhibitor PD0332991, inducing a remarkable G 1 arrest, and downregulation of its downstream targets pRB1 and EZH2. We therefore conclude that CDK6 is indeed a direct target of MLL fusion proteins, playing an important role in the proliferation advantage of MLL-rearranged ALL cells.

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