Pawar Aishwarya S, Somers Patrick, Alex Aleena, Grana Jason, Feist Victoria K, George Subin S, Jalnapurkar Sapana S, Antony Charles, Verner Roman, White-Brown Sanese K, Khera Mohit, Mendoza-Figueroa María Saraí, Liu Kathy Fange, Morrissette Jennifer J D, Gurbuxani Sandeep, Paralkar Vikram R
Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Biomedical Graduate Studies, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Genes Dev. 2025 Jul 28. doi: 10.1101/gad.352602.125.
Myeloid leukemias are heterogeneous cancers with diverse mutations, sometimes in genes with unclear roles and unknown functional partners. PHF6 and PHIP are two poorly understood chromatin-binding proteins recurrently mutated in acute myeloid leukemia (AML). mutations are associated with poorer outcomes, whereas was recently identified as the most common selective mutation in Black patients with AML. Here, we show that knockout converts -driven mouse chronic myelomonocytic leukemia (CMML) into AML with reduced survival. Using cell line models, we show that PHF6 is a transcriptional repressor that suppresses a limited stemness gene network and that missense mutations, classified by current clinical algorithms as variants of unknown significance, produce unstable or nonfunctional protein. We present multiple lines of evidence converging on a critical mechanistic connection between PHF6 and PHIP. We show that loss phenocopies loss and that PHF6 requires PHIP to occupy chromatin and exert its downstream transcriptional program. Our work unifies PHF6 and PHIP, two disparate leukemia mutated proteins, into a common functional complex that suppresses AML stemness.
髓系白血病是具有多种突变的异质性癌症，这些突变有时发生在作用不明且功能伙伴未知的基因中。PHF6和PHIP是两种在急性髓系白血病（AML）中经常发生突变但了解较少的染色质结合蛋白。这些突变与较差的预后相关，而最近PHF6被确定为黑人AML患者中最常见的选择性突变。在这里，我们表明敲除PHF6会将PHIP驱动的小鼠慢性粒单核细胞白血病（CMML）转化为生存期缩短的AML。使用细胞系模型，我们表明PHF6是一种转录抑制因子，可抑制有限的干性基因网络，并且根据当前临床算法分类为意义未明变异体的PHF6错义突变会产生不稳定或无功能的蛋白质。我们提供了多条证据，表明PHF6和PHIP之间存在关键的机制联系。我们表明，PHF6缺失模拟了PHIP缺失，并且PHF6需要PHIP才能占据染色质并发挥其下游转录程序。我们的工作将PHF6和PHIP这两种不同的白血病突变蛋白统一到一个抑制AML干性的共同功能复合物中。
