Murine B-1 B Cell Progenitors Initiate B-Acute Lymphoblastic Leukemia with Features of High-Risk Disease

Montecino‐Rodriguez, Encarnacion; Li, Katy; Fice, Michael P.; Dorshkind, Kenneth

doi:10.4049/jimmunol.1303170

Cited by 20 publications

(21 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, additional mechanisms may also be operative (Wei et al, 2014). For example, B-1 progenitors are much more proliferative than B-2 progenitors (Montecino-Rodriguez et al, 2014). Because, PU.1 intracellular concentrations can be regulated through lengthening of the cell cycle, the Sfpi1 levels in B-1 progenitors may be influenced by their high proliferation (Kueh et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Distinct Genetic Networks Orchestrate the Emergence of Specific Waves of Fetal and Adult B-1 and B-2 Development

et al. 2016

Self Cite

View full text Add to dashboard Cite

SUMMARY B cell development is often depicted as a linear process initiating in the fetus and continuing postnatally. Using a PU.1 hypomorphic mouse model, we found that B-1 and B-2 lymphopoiesis occurred in distinct fetal and adult waves differentially dependent on the Sfpi1 14 kB upstream regulatory element. The initial wave of fetal B-1 development was absent in PU.1 hypomorphic mice, while subsequent fetal and adult waves emerged. In contrast, B-2 lymphopoiesis occurred in distinct fetal and adult waves. Whole transcriptome profiling of fetal and adult B cell progenitors supported the existence of three waves of B-1 and two waves of B-2 development, and revealed that the network of transcription factors governing B lineage specification and commitment was highly divergent between B-1 and B-2 progenitors. These findings support the view that the B-1 and B-2 lineages are distinct and provide a genetic basis for layering of immune system development.

show abstract

Section: Discussionmentioning

confidence: 99%

Distinct Genetic Networks Orchestrate the Emergence of Specific Waves of Fetal and Adult B-1 and B-2 Development

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…They showed that mice transplanted with BCR-ABLtransduced fetal liver or BM B-1 progenitors became moribund more rapidly than recipients of BCR-ABL-transduced B-2 progenitors, suggesting B-1 progenitors as the target cell for disease initiation. 122 Conversely, there are no data about the phenotype of the LIC. The LIC may be distinct from the cell in which MA4 has a preleukemic impact and, this in turn, may also differ from the cell in which MA4 first arises.…”

Section: Available Disease Models For T(4;11) 1 B-allmentioning

confidence: 99%

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

Sanjuán-Pla

Bueno

Prieto

et al. 2015

Blood

105

138

View full text Add to dashboard Cite

Infant B-cell acute lymphoblastic leukemia (B-ALL) accounts for 10% of childhood ALL. The genetic hallmark of most infant B-ALL is chromosomal rearrangements of the mixed-lineage leukemia (MLL) gene. Despite improvement in the clinical management and survival (∼85-90%) of childhood B-ALL, the outcome of infants with MLL-rearranged (MLL-r) B-ALL remains dismal, with overall survival <35%. Among MLL-r infant B-ALL, t(4;11)+ patients harboring the fusion MLL-AF4 (MA4) display a particularly poor prognosis and a pro-B/mixed phenotype. Studies in monozygotic twins and archived blood spots have provided compelling evidence of a single cell of prenatal origin as the target for MA4 fusion, explaining the brief leukemia latency. Despite its aggressiveness and short latency, current progress on its etiology, pathogenesis, and cellular origin is limited as evidenced by the lack of mouse/human models recapitulating the disease phenotype/latency. We propose this is because infant cancer is from an etiologic and pathogenesis standpoint distinct from adult cancer and should be seen as a developmental disease. This is supported by whole-genome sequencing studies suggesting that opposite to the view of cancer as a “multiple-and-sequential-hit” model, t(4;11) alone might be sufficient to spawn leukemia. The stable genome of these patients suggests that, in infant developmental cancer, one “big-hit” might be sufficient for overt disease and supports a key contribution of epigenetics and a prenatal cell of origin during a critical developmental window of stem cell vulnerability in the leukemia pathogenesis. Here, we revisit the biology of t(4;11)+ infant B-ALL with an emphasis on its origin, genetics, and disease models.

show abstract

“…Interestingly, chronic lymphocytic leukemia (CLL) cells from humans and mice express CD5, suggesting their possible origin from B‐1 cells. In addition, B‐1 cells expressing the BCR‐ABL oncogene give rise to acute lymphocytic leukemia and do so more rapidly than their B‐2 counterparts expressing the same oncogene . B‐1 cells constitutively produce interleukin 10 (IL‐10), an immunoregulatory cytokine.…”

Section: Introductionmentioning

confidence: 99%

Role of B cell receptor signaling in IL‐10 production by normal and malignant B‐1 cells

Alhakeem

Sindhava

McKenna

et al. 2015

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

B-1 cells are considered innate immune cells that produce the majority of natural antibodies. B-1 cell responses to B cell receptor (BCR) and Toll-like receptor (TLR) ligation are tightly regulated owing to the cross-reactivity to self-antigens. CD5 has been shown to play a major role in down regulation of BCR responses in B-1 cells. Here, we provide evidence for another mechanism by which BCR response is regulated in B-1 cells. B-1 cells, as well as their malignant counterpart B cell chronic lymphocytic leukemia (CLL) cells, produce interleukin-10 (IL-10) constitutively. IL-10 secretion by normal B-1 cells downregulates their proliferation responses to BCR ligation. However, we found that CLL cells appear to be unique in not responding to IL-10–mediated feedback-suppressive effects in comparison to normal B-1 cells. In addition, we describe a novel role of the B cell receptor signaling pathway in constitutive IL-10 secretion by normal and malignant B-1 cells. We found that inhibition of Src family kinases, spleen tyrosine kinase, Syk, or Bruton's tyrosine kinase (Btk) reduces constitutive IL-10 production by both normal and malignant B-1 cells.

show abstract

Murine B-1 B Cell Progenitors Initiate B-Acute Lymphoblastic Leukemia with Features of High-Risk Disease

Cited by 20 publications

References 32 publications

Distinct Genetic Networks Orchestrate the Emergence of Specific Waves of Fetal and Adult B-1 and B-2 Development

Distinct Genetic Networks Orchestrate the Emergence of Specific Waves of Fetal and Adult B-1 and B-2 Development

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

Role of B cell receptor signaling in IL‐10 production by normal and malignant B‐1 cells

Contact Info

Product

Resources

About