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    • Non supervised clustering of gene expression divided the ALL

    2018-11-09

    Non-supervised clustering of gene expression divided the ALLs into eight subgroups. It will be interesting to learn if these subgroups overlap with the ones reported by Harvey et al. for an American cohort for pediatric ALLs (). The most significant findings are the discoveries of in-frame fusions of , and genes respectively, each creating a separate subgroup characterized by a distinct gene expression profile. These discoveries are highly complementary to those recently reported by a similar study of ALL in AYA in Japan that has just been published (). Single patients with either or fusion translocations have been reported before () but these are the first large studies describing the significance of these fusions in pediatric and adult ALLs. Herein I will discuss these three important novel subtypes of ALL in light of the findings by both groups. Myocyte Enhancer Factor 2D (MEF2D) is a member of a family of transcription factors that participate in neuronal development and myogenesis. The N-terminus of was fused to one of several partners, most commonly , in about 7% of the patients, mostly adolescents. The immunophenotype and gene expression of leukemias were very similar to pre-B ALL caused by the translocation with high expression of , a known target of MEF2D. Expression of fusion in mouse hematopoietic Monastrol arrested B cell differentiation. Although extra caution should be taken on assigning prognostic significance outside a controlled clinical trial, both the Chinese and the Japanese papers noted extremely bad prognosis to the fusion ALLs suggesting a need for better therapies. It will be interesting to learn if pre-B ALL will be sensitive to Dasatinib, SYK inhibitors or other drugs targeting the pre-B cell receptor pathway as was recently reported by the Muschen group (). The second subgroup is characterized by in-frame fusion of one of several genes, most notably or , to , detected in 7–12% of the AYA and older patients. has been shown before to regulate the expression of genes encoding extracellular matrix proteins. Unlike the fusion leukemias, fusions characterized very early pro-B ALL, often CD10 negative with expression of myeloid markers and activation of the JAK-STAT pathway. Consistent with these findings ectopic expression of the translocations in mouse hematopoietic progenitors arrested B cell differentiation and caused monoblastic leukemias. However, unlike other Pro-B ALLs, most notably MLL fusion leukemias, it seems from both studies that the prognosis of this ZNF384 fusion ALLs is relatively good. The third novel discovery is the subgroup of ALL characterized by translocations of the Double Homeobox 4 gene, , into the enhancer locus. is located within a repeat array in the subtelomeric region of chromosome 4q and encodes the transcriptional activator PITX1 (). Contraction of these repeats is associated with autosomal dominant facioscapulohumeral muscular dystrophy (FSHD). The Tokyo group discovered that the translocation to the locus, presented in 10 of 70 AYA patients with ALL, led to high expression of DUX4 with modified C terminus. Significantly, they demonstrated that transduction of mouse pro-B progenitors with fusion gene caused B cell leukemia in mice. They also discovered the translocation in the B ALL cell line NALM6 and showed that DUX4 was necessary for its growth and survival (). In addition to the newly discovered DUX4 translocation, NALM6 contains a microdeletion in the gene (). Interestingly the Shanghai group discovered that nearly all the DUX4 ALLs had also deletions. Microdeletions within the gene have been identified in about 5% of childhood ALL. They are characterized with aberrant CD2 expression and despite common presence of IKZF1 deletions they have excellent prognosis. The microdeletions within are often associated with aberrant transcripts of ERG that have been suggested to be oncogenic. Yet these aberrant transcripts are not always expressed and ERG deletions are often subclonal and disappear in relapse (). These mysterious observations have led to the suggestion that “ERG deletions” ALLs may actually be caused by another driving genomic aberration. The findings by Liu et al. that the recently discovered oncogenic cryptic translocations almost always occur in deleted leukemias suggest either that DUX4 is the oncogenic driving event or that DUX4 cooperates with ERG aberrant isoform in the leukemogenesis process.