Hasan Issa

Bio: Hasan Issa is an academic researcher from Martin Luther University of Halle-Wittenberg. The author has contributed to research in topics: Myeloid leukemia & Haematopoiesis. The author has an hindex of 1, co-authored 3 publications receiving 3 citations.

The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis

Abstract: Given the plasticity of hematopoietic stem/progenitor cells, multiple routes of differentiation must be blocked during acute myeloid leukemia pathogenesis - the molecular basis of which is incompletely understood. Here we report that post-transcriptional repression of transcription factor ARID3A by miR-125b is a key event in megakaryoblastic leukemia (AMKL) pathogenesis. AMKL is frequently associated with trisomy 21 and GATA1 mutations (GATA1s), and children with Down syndrome are at a high risk of developing this disease. We show that chromosome 21-encoded miR-125b synergizes with Gata1s to drive leukemogenesis in this context. Leveraging forward and reverse genetics, we uncover Arid3a as the main miR-125b target underlying this synergy. We demonstrate that during normal hematopoiesis this transcription factor promotes megakaryocytic differentiation in concert with GATA1 and mediates TGF{beta}-induced apoptosis and cell cycle arrest in complex with SMAD2/3. While Gata1s mutations perturb erythroid differentiation and induce hyperproliferation of megakaryocytic progenitors, intact ARID3A expression assures their megakaryocytic differentiation and growth restriction. Upon knockdown, these tumor suppressive functions are revoked, causing a dual megakaryocytic/erythroid differentiation blockade and subsequently AMKL. Inversely, restoring ARID3A expression relieves the megakaryocytic differentiation arrest in AMKL patient-derived xenografts. This work illustrates how mutations in lineage-determining transcription factors and perturbation of post-transcriptional gene regulation interplay to block multiple routes of hematopoietic differentiation and cause leukemia. Surmounting this differentiation blockade in megakaryoblastic leukemia by restoring the tumor suppressor ARID3A represents a promising strategy for treating this lethal pediatric disease. Key pointsO_LIRepression of megakaryocytic transcription factor ARID3A by miR-125b synergizes with GATA1s to induce leukemia C_LIO_LIRestoring ARID3A expression relieves megakaryocytic differentiation arrest in megakaryoblastic leukemia C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/440795v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@146c2a7org.highwire.dtl.DTLVardef@9599fdorg.highwire.dtl.DTLVardef@1b0d22borg.highwire.dtl.DTLVardef@1b61447_HPS_FORMAT_FIGEXP M_FIG C_FIG

Myeloid leukemia vulnerabilities at CTCF-enriched long noncoding RNA loci

Abstract: The noncoding genome presents a largely untapped source of biological insights, including thousands of long noncoding RNA (lncRNA) loci. While some produce bona fide lncRNAs, others exert transcript-independent cis-regulatory effects, and the lack of predictive features renders mechanistic dissection challenging. Here, we describe CTCF-enriched lncRNA loci (C-LNC) as a subclass of functional genetic elements exemplified by MYNRL15, a pan-myeloid leukemia dependency identified by an lncRNA-based CRISPRi screen. MYNRL15 perturbation selectively impairs acute myeloid leukemia (AML) cells over hematopoietic stem / progenitor cells in vitro, and depletes AML xenografts in vivo. Mechanistically, we show that crucial DNA elements in the locus mediate its phenotype, triggering chromatin reorganization and downregulation of cancer dependency genes upon perturbation. Elevated CTCF density distinguishes MYNRL15 and 531 other lncRNA loci in K562 cells, of which 43-54% associate with clinical aspects of AML and 18.4% are functionally required for leukemia maintenance. Curated C-LNC catalogs in other cell types will help refine the search for noncoding oncogenic vulnerabilities in AML and other malignancies.

Integrative Genomics Viewer

Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Activation of proto-oncogenes by disruption of chromosome neighborhoods

Abstract: The spread of bad neighborhoods Our genomes have complex three-dimensional (3D) arrangements that partition and regulate gene expression. Cancer cells frequently have their genomes grossly rearranged, disturbing this intricate 3D organization. Hnisz et al. show that the disruption of these 3D neighborhoods can bring oncogenes under the control of regulatory elements normally kept separate from them (see the Perspective by Wala and Beroukim). These novel juxtapositions can result in the inappropriate activation of oncogenes. Science, this issue p. 1454; see also p. 1398 Disrupting the boundaries between three-dimensional neighborhoods in the genome can activate cancer-promoting genes. [Also see Perspective by Wala and Beroukim] Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes. Perturbation of such boundaries in nonmalignant cells was sufficient to activate proto-oncogenes. Mutations affecting chromosome neighborhood boundaries were found in many types of cancer. Thus, oncogene activation can occur via genetic alterations that disrupt insulated neighborhoods in malignant cells.

Hepatic ARID3A facilitates liver cancer malignancy by cooperating with CEP131 to regulate an embryonic stem cell-like gene signature

Abstract: Liver cancer stemness refers to the stem cell-like phenotype of hepatocarcinoma cells and is closely related to a high degree of tumour malignancy. Here, we identified AT-rich interacting domain 3A (ARID3A) as one of the most upregulated stemness-related transcription factors in liver cancer by an in vitro functional screen. ARID3A can promote liver cancer cell viability and metastasis both in vitro and in vivo. Mechanistically, ARID3A interacts with CEP131 and transcriptionally activates KDM3A by co-occupying its promoter element, further upregulating the expression of downstream embryonic stem (ES) signature genes via demethylation of H3K9me2. ARID3A and CEP131 promote an ES cell gene signature through activation of KDM3A and contribute to the poor prognosis of liver cancer patients. Collectively, these results provide evidence highlighting a transcription-dependent mechanism of ARID3A in stemness regulation in liver cancer. The ARID3A/CEP131-KDM3A regulatory circuit could serve as a prognostic indicator and potential therapeutic target for liver cancer.