Classifying Medulloblastoma Subgroups Based on Small, Clinically Achievable Gene Sets

As treatment protocols for medulloblastoma (MB) are becoming subgroup-specific, means for reliably distinguishing between its subgroups are a timely need. Currently available methods include immunohistochemical stains, which are subjective and often inconclusive, and molecular techniques—e.g., NanoString, microarrays, or DNA methylation assays—which are time-consuming, expensive and not widely available. Quantitative PCR (qPCR) provides a good alternative for these methods, but the current NanoString panel which includes 22 genes is impractical for qPCR. Here, we applied machine-learning–based classifiers to extract reliable, concise gene sets for distinguishing between the four MB subgroups, and we compared the accuracy of these gene sets to that of the known NanoString 22-gene set. We validated our results using an independent microarray-based dataset of 92 samples of all four subgroups. In addition, we performed a qPCR validation on a cohort of 18 patients diagnosed with SHH, Group 3 and Group 4 MB. We found that the 22-gene set can be reduced to only six genes (IMPG2, NPR3, KHDRBS2, RBM24, WIF1, and EMX2) without compromising accuracy. The identified gene set is sufficiently small to make a qPCR-based MB subgroup classification easily accessible to clinicians, even in developing, poorly equipped countries

An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis "ph-like" BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (CDKN2A) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.This work was supported by the Israel Science Foundation (# 1178/12 to S.I.), Children with Cancer (UK) (S.I. and T.E.), Swiss Bridge Foundation (S.I.), WLBH Foundation (S.I.), Waxman Cancer Research Foundation (S.I.), US–Israel Binational Science Foundation, Israeli health ministry ERA-NET program (#CANCER11-FP-127 to S.I.), Hans Neufeld Stiftung, the International Collaboration Grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program, a partnership of the Israel Cancer Research Fund and City of Hope (S.I. grants # 00161), the Nevzlin Genomic Center for Precision Medicine in Schneider Children’s Medical Center of Israel, The European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 813091 (S.I.) and the Israel Childhood Cancer Foundation (S.I.). I.G. was partially supported by Israeli ministry of Immigrant Absorption.info:eu-repo/semantics/publishedVersio

Metabolic adaptation of acute lymphoblastic leukemia to the central nervous system microenvironment depends on Stearoyl CoA desaturase

Metabolic reprogramming is a key hallmark of cancer, but less is known about metabolic plasticity of the same tumor at different sites. Here, we investigated the metabolic adaptation of leukemia in two different microenvironments, the bone marrow and the central nervous system (CNS). We identified a metabolic signature of fatty acid synthesis in CNS leukemia, highlighting stearoyl-CoA desaturase (SCD) as a key player. In vivo SCD overexpression increases CNS disease, whereas genetic or pharmacological inhibition of SCD decreases CNS load. Overall, we demonstrated that leukemic cells dynamically rewire metabolic pathways to suit local conditions and that targeting these adaptations can be exploited therapeutically

Mitotic Phosphorylation of Chromosomal Protein HMGN1 Inhibits Nuclear Import and Promotes Interaction with 14.3.3 Proteins

Progression through mitosis is associated with reversible phosphorylation of many nuclear proteins including that of the high-mobility group N (HMGN) nucleosomal binding protein family. Here we use immunofluorescence and in vitro nuclear import studies to demonstrate that mitotic phosphorylation of the nucleosomal binding domain (NBD) of the HMGN1 protein prevents its reentry into the newly formed nucleus in late telophase. By microinjecting wild-type and mutant proteins into the cytoplasm of HeLa cells and expressing these proteins in HmgN1(−/−) cells, we demonstrate that the inability to enter the nucleus is a consequence of phosphorylation and is not due to the presence of negative charges. Using affinity chromatography with recombinant proteins and nuclear extracts prepared from logarithmically growing or mitotically arrested cells, we demonstrate that phosphorylation of the NBD of HMGN1 promotes interaction with specific 14.3.3 isotypes. We conclude that mitotic phosphorylation of HMGN1 protein promotes interaction with 14.3.3 proteins and suggest that this interaction impedes the reentry of the proteins into the nucleus during telophase. Taken together with the results of previous studies, our results suggest a dual role for mitotic phosphorylation of HMGN1: abolishment of chromatin binding and inhibition of nuclear import