Acute Lymphoblastic Leukemia - PHF6 Interacts with the LMO2 Complex in T-cell Acute Lymphoblastic Leukemia

Sep 29, 2026

Uploaded by Riley

The transcriptional mediator LMO2 forms a multi-protein complex with TAL1/LYL1, HEB/E2A, LDB1 and GATA, coordinating gene regulation from hematopoietic development through differentiation. Chromosomal rearrangements involving LMO2 and TAL1 drive T-cell lymphoblastic leukemia (T-ALL). PHF6 is identified as a new LMO2-interacting factor, with leukemia-associated somatic mutations across multiple hematologic malignancies. PHF6 binds DNA and associates with the TAL1/LMO2/LDB1/GATA2 complex to regulate key blood-development genes such as SPI1 (PU.1).

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Abstract

Introduction

Methods

Cell culture

Patient samples

Immunoprecipitation

ARTICLE-Acute Lymphoblastic Leukemia PHF6 interacts with the LMO2 complex in T-cell acute lymphoblastic leukemia Vesna S. Stanulović,1,2* Sarah Binhassan,1,2* Budoor A. Jaber,1 Shimaa Alazmi,1,2 Fatma M. B. Saleman,1,2 Sandeep Potluri,1,2 Guy Pratt,1,3 Christian Ludwig,4 Douglas G. Ward1 and Maarten Hoogenkamp1,2 1 Department of Cancer and Genomics Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham; 2 Birmingham Center for Genome Biology, University of Birmingham; 3Center for Clinical Hematology, Queen Elizabeth Hospital Birmingham and 4 Department of Metabolism and Systems Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK Correspondence: M. Hoogenkamp [m.hoogenkamp@bham.ac.uk](m.hoogenkamp@bham.ac.uk) [Received:](Received: December 5)[ December 5](Received: December 5), 2024. Accepted: June 24, 2025. Early view: July 10, 2025. [https://doi.org/10.3324/haematol.2024.287124](https://doi.org/10.3324/haematol.2024.287124) ©2026 Ferrata Storti Foundation Published under a CC BY-NC license *VSS and SB contributed equally as first authors. Abstract The transcriptional mediator LIM domain only 2 (LMO2) forms a large multi-protein complex together with TAL1/LYL1, HEB/ E2A, LDB1 and GATA. This complex regulates transcription from the onset of hematopoietic development and during differentiation. Chromosomal re-arrangements involving LMO2 and TAL1 are causative for T-cell lymphoblastic leukemia (T-ALL) . We have identified Plant Homeodomain (PHD)-like Finger 6 (PHF6) as a new LMO2-interacting factor. Somatic mutations in PHF6 have been found to occur in several types of leukemia. We show that PHF6 interacts with LMO2 as a part of the TAL1, GATA2, LDB1 complex in T-ALL and binds to the DNA. These findings show that PHF6 associates with the TAL1/LMO2/LDB1/ GATA2 complex and regulates genes that have a major role in blood development, such as SPI1 (PU.1) . Introduction LIM domain only 2 (LMO2) is a protein that mediates interactions between the transcription factors GATA and a heterodimer composed of TAL1 or LYL1 and HEB or E2A. The essential role of the LMO2 complex in hematopoiesisis facilitated through the ability of LDB1 to trimerize and facilitate long range interactions between distal regulatory DNA elements 1,2 This transcriptional complex regulates gene expression of many hematopoietic and non-hematopoietic genes.3,4 In hematopoietic development, LMO2 is expressed from the haemangioblast stage, in hematopoietic stem and progenitor cells and downregulated during differentiation, except in the erythroid lineage.5-7 During T-cell development, LMO2 and TAL1 are downregulated in double-negative (CD4-CD8-) thymocytes.8 Recurrent chromosomal aberrations involving LMO2 and TAL1 (45-50% of T-cell lymphoblastic leukemia [T-ALL]) result in their overexpression and lead to the development of T-ALL.9-11 Gene expression profiling analysis on pediatric T-ALL patient samples showed that cases with TAL/LMO rearrangements constitute a separate cluster which accounts for 45-50% of T-ALL 12,13 Human PHD finger protein 6 (PHF6) is a nuclear and nucleolar protein involved in suppression of rRNA expression, chromatin remodeling, DNA repair, H2B ubiquitination, and transcriptional regulation 14-20 Germline mutations in PHF6 cause X-linked Börjeson-Forssman-Lehmann syndrome, a rare form of syndromic intellectual disability (BFLS; OMIM301900) . Somatic PHF6 mutations are found in 18% of pediatric and 36% of adult T-ALL, 2-3% of acute myeloid leukemia (AML), 16-55% of mixed phenotype acute leukemia (MPAL) and small numbers of chronic myeloid leukemia (CML) and high-grade B-cell lymphoma (HGBL) 14,21-26 While BFLS mutations are missense mutations occurring throughout the coding region or C-terminal nonsense mutations, the mutations observed in leukemia are predominantly nonsense and frame shifts spread throughout the co

FAQs

What protein complex does LMO2 form, and what is its biological role?

LMO2 forms a multi-protein complex with TAL1/LYL1, HEB/E2A, LDB1 and GATA. The complex regulates transcription during hematopoietic development and differentiation.

How is PHF6 related to LMO2 in T-ALL?

PHF6 is identified as a new LMO2-interacting factor. In T-ALL, PHF6 interacts with LMO2 as part of the TAL1, GATA2, LDB1 complex and binds DNA to influence transcriptional regulation.

Which gene highlighted in the document is regulated by the PHF6-associated complex?

The document indicates that PHF6 regulates genes with major roles in blood development, including SPI1 (PU.1).

Sep 29, 2026

Uploaded by Riley