MYB Haploinsufficiency Causes Familial Autoimmune Cytopenias

MYB is a transcription factor and master regulator of hematopoiesis with a central role at multiple stages of B and T cell development. We identified ten heterozygous germline MYB variants in seven families and four unrelated singletons. The variants segregated with autoimmune cytopenias, including Evans syndrome, in three five-generation pedigrees. In our cohort of 41 carriers, 22 were affected by autoimmune cytopenias, while one had isolated B cell lymphopenia and neutropenia. All ten variants are absent or ultra-rare in population databases and segregate with disease in the kindreds in an autosomal-dominant pattern with incomplete penetrance. In silico analyses predict that the variants are likely to perturb MYB function. Carriers of select alleles (p.R81X, c.1587+1G>C, p.S407Vfs*13, and c.528-1G>T) from whom biospecimens were available exhibited elevated fetal hemoglobin levels, consistent with reduced MYB function given its established role as a fetal hemoglobin repressor. For the p.R81X and p.S407Vfs*13 alleles, we demonstrated reduced protein expression in activated CD8+ T cells, supporting MYB haploinsufficiency as the underlying mechanism. High-resolution immunophenotyping of carriers of the p.R81X, c.1587+1G>C, and p.S407Vfs*13 alleles revealed expanded T-bet-positive B cells and expanded CD4+ and CD8+ terminal effector T cells, suggesting that reduced MYB function affects lymphocyte differentiation pathways relevant to immune regulation. Together, the segregation, computational, functional, and immunophenotypic data establish damaging germline MYB variants as a dominantly inherited cause of autoimmune cytopenias, expand the spectrum of inborn errors of immunity, and support an immunoregulatory role for MYB in activated lymphocytes.

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Journal
Journal of Human Immunity
Published
2026-05-01
DOI
https://doi.org/10.70962/cis2026abstract.16
Primary Topic
Blood disorders and treatments
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article
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article

MYB Haploinsufficiency Causes Familial Autoimmune Cytopenias

Àngela Deyà‐Martínez, Étienne Crickx, J A Lee, James L. Zehnder et al.
Journal of Human Immunity
Blood disorders and treatments
article

MYB Haploinsufficiency Causes Familial Autoimmune Cytopenias

Àngela Deyà‐Martínez, Étienne Crickx, J A Lee, James L. Zehnder, Yagiz Anasiz, Laia Alsina, Siobhan Cross, Ben R. Saxon, Lori Broderick, Ashley V. Geerlinks, Hamish S. Scott, Jackie L. Ludgate, Stuart E. Turvey, Richard Dandrea, Robert J. Weeks, Süleyman Gülsüner, Christopher N Hahn, Ian M. Morison, Michael J. Bamshad, Rubén Martínez‐Barricarte, Jessica X. Chong, Debbie Jiang, Thomas J. Gonda, Cassandra McDonald, Parvathy Venugopal, Aaron B. Boothby, Nicola K. Poplawski, Taylor K. Watson, Munusamy Ponnan Sivasankaran, Michael Osborn, Matthew Bainbridge, Ana García-García, Bing M. Zhang, Kerry Lannert, Jeffery W. Zhong, Jenny Kim, Eric Allenspach, Lauren E. Brown, Frederic Rieux-Laucat, Diana G. Fisk, Jill Johnson, Siobán Keel, David Yao, Abhi Kulkarni, Shaun Jackson
article en

Abstract

MYB is a transcription factor and master regulator of hematopoiesis with a central role at multiple stages of B and T cell development. We identified ten heterozygous germline MYB variants in seven families and four unrelated singletons. The variants segregated with autoimmune cytopenias, including Evans syndrome, in three five-generation pedigrees. In our cohort of 41 carriers, 22 were affected by autoimmune cytopenias, while one had isolated B cell lymphopenia and neutropenia. All ten variants are absent or ultra-rare in population databases and segregate with disease in the kindreds in an autosomal-dominant pattern with incomplete penetrance. In silico analyses predict that the variants are likely to perturb MYB function. Carriers of select alleles (p.R81X, c.1587+1G>C, p.S407Vfs*13, and c.528-1G>T) from whom biospecimens were available exhibited elevated fetal hemoglobin levels, consistent with reduced MYB function given its established role as a fetal hemoglobin repressor. For the p.R81X and p.S407Vfs*13 alleles, we demonstrated reduced protein expression in activated CD8+ T cells, supporting MYB haploinsufficiency as the underlying mechanism. High-resolution immunophenotyping of carriers of the p.R81X, c.1587+1G>C, and p.S407Vfs*13 alleles revealed expanded T-bet-positive B cells and expanded CD4+ and CD8+ terminal effector T cells, suggesting that reduced MYB function affects lymphocyte differentiation pathways relevant to immune regulation. Together, the segregation, computational, functional, and immunophenotypic data establish damaging germline MYB variants as a dominantly inherited cause of autoimmune cytopenias, expand the spectrum of inborn errors of immunity, and support an immunoregulatory role for MYB in activated lymphocytes.

Journal of Human ImmunityVol. 2(CIS2026)
South Australia Pathology (AU), Center for Infectious Disease Research (US), Hospital Sant Joan de Déu Barcelona (ES), Children’s Institute (US), Cancer Prevention Institute of California (US), University of British Columbia (CA), University of South Australia (AU), Université Paris-Est Créteil (FR), Vanderbilt University (US), University of Washington (US), London Health Sciences Centre (CA), Women's and Children's Hospital (AU), Christchurch Hospital (NZ), Rady Children's Hospital-San Diego (US), Cancer Australia (AU), Massachusetts General Hospital (US), Seattle Children's Hospital (US), Hôpitaux Universitaires Henri-Mondor (FR), Stanford Medicine (US), Centre for Cancer Biology (AU), Institut des Maladies Génétiques Imagine (FR), University of Otago (NZ), Vanderbilt University Medical Center (US), Stanford University (US)
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