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A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program.

ABSTRACT: Although 90% of children with acute lymphoblastic leukemia (ALL) are now cured, the prognosis for infant-ALL remains dismal. Infant-ALL is usually caused by a single genetic hit that arises in utero: an MLL/KMT2A gene rearrangement (MLL-r). This is sufficient to induce a uniquely aggressive and treatment-refractory leukemia compared to older children. The reasons for disparate outcomes in patients of different ages with identical driver mutations are unknown. Using the most common MLL-r in infant-ALL, MLL-AF4, as a disease model, we show that fetal-specific gene expression programs are maintained in MLL-AF4 infant-ALL but not in MLL-AF4 childhood-ALL. We use CRISPR-Cas9 gene editing of primary human fetal liver hematopoietic cells to produce a t(4;11)/MLL-AF4 translocation, which replicates the clinical features of infant-ALL and drives infant-ALL-specific and fetal-specific gene expression programs. These data support the hypothesis that fetal-specific gene expression programs cooperate with MLL-AF4 to initiate and maintain the distinct biology of infant-ALL.

SUBMITTER: Rice S

PROVIDER: S-EPMC8616957 | biostudies-literature |

REPOSITORIES: biostudies-literature

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HOXA9/IRX1 expression pattern defines two subgroups of infant MLL-AF4-driven acute lymphoblastic leukemia.

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Foetal-specific contributors to infant MLL-AF4-driven Acute Lymphoblastic Leukaemia

Project description:As MLL-rearranged infant leukaemia is known to initiate in utero, we sought to identify developemntal genes expressed in foetal cells that may aid leukaemogenesis. Bulk RNA-Seq was therefore carried out on mouse and human foetal liver blood progenitors (lymphoid-primed multipotent progenitors [LMPPs] and haematopoietic stem cells/ multipotent progenitor cells [HSC/MPPs]) and compared with the same cell types isolated from developmentally later human cord blood and mouse adult bone marrow.

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A novel human fetal liver-derived model reveals that MLL-AF4 drives fetal gene expression programs in infant ALL [ChIP-seq]

Project description:Although 90% of children with acute lymphoblastic leukemia (ALL) are now cured, the prognosis of infant-ALL (diagnosis within the first year of life) remains dismal. Infant-ALL is usually caused by a single genetic hit that arises in utero: rearrangement of the MLL/KMT2A gene (MLL-r). This is sufficient to give rise to a uniquely aggressive and treatment-refractory leukemia compared to older children with the same MLL-r. The reasons for disparate outcomes in patients of different ages with identical molecular drivers are unknown. This paper addresses the hypothesis that fetal-specific gene expression programs co-operate with MLL-AF4 to initiate and maintain infant-ALL. Using direct comparison of fetal and adult HSC and progenitor transcriptomes we identify fetal-specific gene expression programs in primary human cells. We show that MLL-AF4-driven infant-ALL, but not MLL-AF4 childhood-ALL, displays expression of fetal-specific genes. In a direct test of this observation, we find that CRISPR-Cas9 gene editing of primary human fetal liver cells (to produce a t(4;11)/MLL-AF4 translocation) replicates the clinical features of infant-ALL and drives infant-ALL-specific and fetal-specific gene expression programs. These data strongly support the hypothesis that fetal-specific gene expression programs co-operate with MLL-AF4 to initiate and maintain the distinct biology of infant ALL.

2021-10-25 | GSE162034 | GEO

Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia: biology and therapeutic targeting.

Project description:Cooperating leukemogenic events in MLL-rearranged (MLL-r) infant acute lymphoblastic leukemia (ALL) are largely unknown. We explored the role of promoter CpG island hypermethylation in the biology and therapeutic targeting of MLL-r infant ALL. The HELP (HpaII tiny fragment enrichment by ligation-mediated polymerase chain reaction [PCR]) assay was used to examine genome-wide methylation of a cohort of MLL-r infant leukemia samples (n = 5), other common childhood ALLs (n = 5), and normals (n = 5). Unsupervised analysis showed tight clustering of samples into their known biologic groups, indicating large differences in methylation patterns. Global hypermethylation was seen in the MLL-r cohort compared with both the normals and the others, with ratios of significantly (P < .001) hypermethylated to hypomethylated CpGs of 1.7 and 2.9, respectively. A subset of 7 differentially hypermethylated genes was assayed by quantitative reverse-transcription (qRT)-PCR, confirming relative silencing in 5 of 7. In cell line treatment assays with the DNA methyltransferase inhibitor (DNMTi) decitabine, MLL-r (but not MLL wild-type cell lines) showed dose- and time-dependent cytotoxicity and re-expression of 4 of the 5 silenced genes. Methylation-specific PCR (MSP) confirmed promoter hypermethylation at baseline, and a relative decrease in methylation after treatment. DNMTi may represent a novel molecularly targeted therapy for MLL-r infant ALL.

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CircRNA study in MLL::AF4 rearranged acute lymphoblastic leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-09-22 | GSE213990 | GEO

Pathogenetic, Clinical, and Prognostic Features of Adult t(4;11)(q21;q23)/MLL-AF4 Positive B-Cell Acute Lymphoblastic Leukemia.

Project description:Translocation t(4;11)(q21;q23) leading to formation of MLL-AF4 fusion gene is found in about 10% of newly diagnosed B-cell acute lymphoblastic leukemia (ALL) in adult patients. Patients expressing this chromosomal aberration present typical biological, immunophenotypic, and clinical features. This form of leukemia is universally recognized as high-risk leukemia and treatment intensification with allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR) could be a valid option to improve prognosis, but data obtained from the literature are controversial. In this review, we briefly describe pathogenetic, clinical, and prognostic characteristics of adult t(4;11)(q21;q23)/MLL-AF4 positive ALL and provide a review of the clinical outcome reported by the most important cooperative groups worldwide.

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HDAC7 is a major contributor in the pathogenesis of t(4;11)/MLL-AF4+ infant B-cell acute lymphoblastic leukemia

Project description:Infants diagnosed of precursor B-cell acute lymphoblastic leukemia (iB-ALL) presenting MLL-AF4 chromosomal rearrangement are at high risk of disease progression into fatal outcome. This specific subtype of pediatric leukemia constitutes a tough challenge in leukemia research, given the difficulties found when trying in vivo modelling. However, the understanding of mechanisms leading to proper lymphocyte generation may become of high utility in gaining deep insight on this malignancy. As we report here, the lack of HDAC7, a key transcriptional regulator in B lymphocyte differentiation, worsens the prognosis of iB-ALL patients. In fact, MLL-AF4+ iB-ALL patients with high expression of HDAC7 display an improved survival, partially mediated by the repression of oncogenes, such as c-MYC, and chemoresistance markers, like the ASNS enzyme. Accordingly, HDAC7 drastically reduces leukemic cells proliferation in MLL-AF4+ iB-ALL through the induction of apoptosis. Moreover, RNA sequencing of HDAC7-overexpressing cells has revealed that HDAC7 alters the genomic profiling of MLL-AF4+ iB-ALL cells towards that of healthy B-cell progenitors. In summary, the findings here reported highlight the role of HDAC7 in predicting prognosis of a lethal subtype of iB-ALL and open new clinical perspectives, since MLL-AF4+ iB-ALL infants would highly benefit from therapeutic options eventually restoring HDAC7 expression.

2021-06-04 | GSE151793 | GEO

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