Shlush Lab

The aging of the human
hematopoietic system

Research

The aging of the human hematopoietic system is typically correlated with: 1) clonal hematopoiesis 2) myeloid malignancies 3) reduced T and B cell clonal diversity 4) reduced myeloid cells function 5) red to yellow marrow transition. Understanding the evolutionary principals driving these phenotypes is the first step in early diagnosis and treatment of hematopoiesis malfunction. Hematopoiesis failure in humans is a long process of somatic selection. Somatic evolution creates new clones exploring the fitness space. Without changes in the somatic environment new clones will loose to the young hematopoietic system which have been optimized over millions of years of germline evolution. Under changing environment, the fittest clones will gradually take over and in time due to antagonistic pleiotropy will lead to a disease. Our lab is a multidisciplinary lab composed of hematologists, evolutionary biologists and computationalsystem biologists all trying to understand the rules of human hematopoietic aging.

Research page

Leukemia early evolution

The functional consequences of preleukemic mutations

The changing environment

Selected Publications

MMS22L is a novel key actor of normal and pathological erythropoiesis

Colin E., Ferrer-Vicens I., Brook D., Salma M., Andrieu-Soler C., Bayard E., Fernandes A., Brouzes C., Lefèvre C., Duval R., Dussiot M., Trovati T., Courtois G., Azouzi S., Zarhrate M., Lambilliotte A., Park S., Carpentier B., Colard M., Manceau S., Moshous D., Mayeux P., Gautier E. F., Miccio A., Soulier J., Vainchenker W., Shlush L., Da Costa L., Frayne J., Soler E., Hermine O. & Couronné L. (2025) HemaSphere. 9, 12, e70264.

The emergence of next-generation sequencing techniques has led to the genetic characterization of numerous congenital erythroid disorders, emphasizing crucial pathways in both normal and pathological erythropoiesis. In this study, whole exome sequencing of a single patient with atypical congenital pure red cell aplasia revealed a mutation in the CDAN1 gene, typically associated with congenital dyserythropoietic anemia type 1 (CDAI), together with a previously unreported mutation in the MMS22L gene. Combined mms22l and cdan1 haploinsufficiency results in severe anemia in a zebrafish model. In human erythroid progenitors, loss of MMS22L leads to proliferation and differentiation arrest associated with activation of the p53 pathway and global epigenetic alterations, showing that MMS22L plays an indispensable role in erythropoiesis. Furthermore, MMS22L and CDAN1 are involved in the same protein complex whose nuclear import is mediated by the importin 4 (IPO4) protein, and MMS22L nuclear import is impaired in CDAI patients due to a defective interaction between CDAN1 and IPO4. Overall, through the genetic description of a single case characterized by digenic inheritance, we identified MMS22L as a novel key factor in erythropoiesis and brought new insights into normal erythropoiesis regulation and CDAI pathophysiology.

Aged B cells as a candidate cell of origin for diffuse large B cell lymphoma: A multi-modal analysis of somatic mutation, clonality, and transcriptional programs

Dadi G., Varon B., Naffaa M., Feldman T., Horowitz N., Kaushansky N. & Shlush L. (2025) Blood. 146, Supplement 1, p. 461-462

Background:The human B cell repertoire is shaped by V(D)J recombination and somatic hypermutation (SHM) for diverse adaptive immunity, but prone to off-target mutagenesis1,2. Activation-induced cytidine deaminase (AID), central to SHM, is classically confined to germinal centers (GCs) but emerging data suggest activity beyond GCs, contributing to off-target mutations3,4. Memory B cells (mB Cells), compared to their naïve counterparts, accumulate more somatic mutations, with patterns reflecting off target SHMpatterns that mirror those seen in B cell lymphomas5. Aged B Cells (ABCs; CD21low/CD11c+/CD18+/T-BET+/ZEB2+), are a memory B cell subset enriched in aging and autoimmunity (AI) shown to express AID outside GCs6-8.Diffuse large B cell lymphoma (DLBCL) is an aggressive malignancy, prevalent in older adults and those with AI or chronic infection9,10. Recent large-scale genomic studies have proposed a complementary classification of DLBCL based on recurrent somatic mutations and indel profileswith characteristic activation-induced cytidine deaminase (AID) mutational footprintsrather than relying solely on cell-of-origin categories. Defining DLBCL subtypes by mutational patterns links the contribution of mutagenesis to DLBCL pathogenesis and suggests opportunities for mutation-based MRD monitoring. We hypothesized that ABCs may serve as a cell of origin for DLBCL.

Mapping circulating hematopoietic stem cells for non-invasive, blood-based diagnostics

Furer N. & Shlush L. (2025) Nature Medicine.

A single-cell-resolution reference atlas of circulating hematopoietic stem and progenitor cells from healthy people reveals variations in cell-population frequencies and transcriptional profiles associated with age and sex. This atlas enables non-invasive diagnosis, risk stratification and follow-up of hematological conditions using peripheral blood, offering a potential alternative to bone marrow sampling.

All Publications