Molecularly distinct models of zebrafish Myc-induced B cell leukemia

AbstractZebrafish models of T cell acute lymphoblastic leukemia (T-ALL) have been studied for over a decade, but curiously, robust zebrafish B cell ALL (B-ALL) models had not been described. Recently, our laboratories reported two seemingly closely-related models of zebrafish B-ALL. In these genetic lines, the primary difference is expression of either murine or human transgenic c-MYC, each controlled by the zebrafish rag2 promoter. Here, we compare ALL gene expression in both models. Surprisingly, we find that B-ALL arise in different B cell lineages, with ighm+ vs. ighz+ B-ALL driven by murine Myc vs. human MYC, respectively. Moreover, these B-ALL types exhibit signatures of distinct molecular pathways, further unexpected dissimilarity. Thus, despite sharing analogous genetic makeup, the ALL types in each model are markedly different, proving subtle genetic changes can profoundly impact model organism phenotypes. Investigating the mechanistic differences between mouse and human c-MYC in these contexts may reveal key functional aspects governing MYC-driven oncogenesis in human malignancies.

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Acute lymphoblastic leukemia with Burkitt cell morphology and cytoplasmic immunoglobulin

Blood ◽

10.1182/blood.v56.2.311.bloodjournal562311 ◽

1980 ◽

Vol 56 (2) ◽

pp. 311-314

Author(s):

DJ Ganick ◽

JL Finlay

Keyword(s):

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Cell Morphology ◽

Lymphoblastic Leukemia ◽

Morphological Characteristics ◽

Cell Leukemia ◽

First Report ◽

Surface Immunoglobulin ◽

B Cell Leukemia

A case of acute lymphoblastic leukemia with morphological characteristics of Burkitt's leukemia (L3 morphology) is presented. This patient's lymphoblasts were lacking in surface immunoglobulin, but were found to contain cytoplasmic IgM. This is the first report of a morphologically B-cell leukemia showing pre-B-cell characteristics immunologically.

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The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer

eLife ◽

10.7554/elife.06377 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 24

Author(s):

Eric Wang ◽

Shinpei Kawaoka ◽

Jae-Seok Roe ◽

Junwei Shi ◽

Anja F Hohmann ◽

...

Keyword(s):

B Cell ◽

Gene Networks ◽

Lymphoblastic Leukemia ◽

Leukemia Cell ◽

Biological Functions ◽

Cell Leukemia ◽

Cis Element ◽

Large Gene ◽

B Cell Leukemia ◽

Essential Function

Most mammalian transcription factors (TFs) and cofactors occupy thousands of genomic sites and modulate the expression of large gene networks to implement their biological functions. In this study, we describe an exception to this paradigm. TRIM33 is identified here as a lineage dependency in B cell neoplasms and is shown to perform this essential function by associating with a single cis element. ChIP-seq analysis of TRIM33 in murine B cell leukemia revealed a preferential association with two lineage-specific enhancers that harbor an exceptional density of motifs recognized by the PU.1 TF. TRIM33 is recruited to these elements by PU.1, yet acts to antagonize PU.1 function. One of the PU.1/TRIM33 co-occupied enhancers is upstream of the pro-apoptotic gene Bim, and deleting this enhancer renders TRIM33 dispensable for leukemia cell survival. These findings reveal an essential role for TRIM33 in preventing apoptosis in B lymphoblastic leukemia by interfering with enhancer-mediated Bim activation.

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Immunophenotyping of Murine Precursor B-Cell Leukemia/Lymphoma: A Comparison of Immunohistochemistry and Flow Cytometry

Veterinary Pathology ◽

10.1177/0300985819852138 ◽

2019 ◽

Vol 56 (6) ◽

pp. 950-958 ◽

Cited By ~ 1

Author(s):

Laura J. Janke ◽

Charles G. Mullighan ◽

Jinjun Dang ◽

Jerold E. Rehg

Keyword(s):

Flow Cytometry ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Surrogate Marker ◽

Cell Development ◽

B Cell Development ◽

Cell Leukemia ◽

B Cell Leukemia ◽

The Common ◽

Viral Mutagenesis

In humans and in mouse models, precursor B-cell lymphoblastic leukemia (B-ALL)/lymphoblastic lymphoma (B-LBL) can be classified as either the pro-B or pre-B subtype. This is based on the expression of antigens associated with the pro-B and pre-B stages of B-cell development. Antigenic markers can be detected by flow cytometry or immunohistochemistry (IHC), but no comparison of results from these techniques has been reported for murine B-ALL/LBL. In our analysis of 30 cases induced by chemical or viral mutagenesis on a WT or Pax5+/–background, 18 (60%) were diagnosed as pro-B by both flow cytometry and IHC. Discordant results were found for 12 (40%); 6 were designated pro-B by IHC and pre-B by flow cytometry and the reverse for the remaining 6 cases. Discordance occurred because different markers were used to define the pro-B–to–pre-B transition by IHC vs flow cytometry. IHC expression of cytoplasmic IgM (μIgM) defined the pre-B stage, whereas the common practice of using CD25 as a surrogate marker in flow cytometry was employed here. These results show that CD25 and μIgM are not always concurrently expressed in B-ALL/LBL, in contrast to normal B-cell development. Therefore, when subtyping B-ALL/LBL in mice, an IHC panel of B220, PAX5, TdT, c-Kit/CD117, CD43, IgM, and ΚLC should be considered. For flow cytometry, cytoplasmic IgM may be an appropriate marker in conjunction with the surface markers B220, CD19, CD43, c-Kit/CD117, BP-1, and CD25.

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MEF2D-BCL9 B-Lymphoblastic Leukemia Blast Morphology Does Not Always Mimic Mature B-Cell Leukemia

Journal of Pediatric Hematology/Oncology ◽

10.1097/mph.0000000000002009 ◽

2020 ◽

Vol Publish Ahead of Print ◽

Author(s):

Hee Jo Baek ◽

Yoon Jung Choi ◽

Bo Ram Kim ◽

Jun Hyung Lee ◽

Myung-Geun Shin ◽

...

Keyword(s):

B Cell ◽

Lymphoblastic Leukemia ◽

Cell Leukemia ◽

Leukemia Blast ◽

B Cell Leukemia

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The rise of apoptosis: targeting apoptosis in hematologic malignancies

Blood ◽

10.1182/blood-2018-02-791350 ◽

2018 ◽

Vol 132 (12) ◽

pp. 1248-1264 ◽

Cited By ~ 39

Author(s):

Rebecca Valentin ◽

Stephanie Grabow ◽

Matthew S. Davids

Keyword(s):

B Cell ◽

Lymphoblastic Leukemia ◽

Myeloid Cell ◽

B Cell Lymphoma ◽

Hematologic Malignancies ◽

Lymphocytic Leukemia ◽

Cell Leukemia ◽

Apoptotic Pathway ◽

Non Hodgkin Lymphoma ◽

B Cell Leukemia

Abstract Dysregulation of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins of the intrinsic apoptotic pathway is fundamental to the pathophysiology of many hematologic malignancies. The BCL-2 family consists of regulatory proteins that either induce apoptosis (proapoptotic) or inhibit it (prosurvival). BCL-2, myeloid cell leukemia-1, and B-cell lymphoma–extra large are prosurvival proteins that are prime targets for anticancer therapy, and molecules targeting each are in various stages of preclinical and clinical development. The US Food and Drug Administration (FDA)-approved BCL-2 inhibitor venetoclax was first proven to be highly effective in chronic lymphocytic leukemia and some B-cell non-Hodgkin lymphoma subtypes. Subsequently, venetoclax was found to be active clinically against a diverse array of hematologic malignancies including multiple myeloma, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, and others. Here, we give a brief introduction to BCL-2 family biology and the mechanism of action of BCL-2 Homology 3 (BH3) mimetics, and provide an overview of the clinical data for therapeutically targeting prosurvival proteins in hematologic malignancies, with a focus on BCL-2 inhibition. To prioritize novel agent combinations and predict responders, we discuss the utility of functional assays such as BH3 profiling. Finally, we provide a perspective on how therapies targeting BCL-2 family proteins may be optimally implemented into future therapeutic regimens for hematologic malignancies.

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Decreased IL-10 accelerates B-cell leukemia/lymphoma in a mouse model of pediatric lymphoid leukemia

Blood Advances ◽

10.1182/bloodadvances.2021005522 ◽

2021 ◽

Author(s):

Briana Fitch ◽

Mi Zhou ◽

Jamilla Situ ◽

Sangeetha Surianarayanan ◽

Melissa Q Reeves ◽

...

Keyword(s):

Mouse Model ◽

B Cell ◽

Inflammatory Responses ◽

Lymphoblastic Leukemia ◽

Dependent Manner ◽

Lymphoid Leukemia ◽

Childhood Infections ◽

Microbial Dysbiosis ◽

B Cell Leukemia ◽

Cell Acute Lymphoblastic Leukemia

Exposures to a wide repertoire of common childhood infections and strong inflammatory responses to those infections are associated with risk of pediatric B-cell acute lymphoblastic leukemia (B-ALL) in opposing directions. Neonatal inflammatory markers are also related to risk by unknown mechanism(s). Here, we demonstrate that IL-10 deficiency, which is associated with childhood B-ALL, indirectly impairs B lymphopoiesis and increases B-cell DNA damage in association with a module of 6 proinflammatory/myeloid-associated cytokines (IL-1α, IL-6, IL-12p40, IL-13, MIP-1β/CCL4, and G-CSF). Importantly, antibiotics attenuated inflammation and B-cell defects in preleukemic Cdkn2a-/-Il10-/- mice. In an ETV6-RUNX1+ (E6R1+) Cdkn2a-/- mouse model of B-ALL, decreased levels of IL-10 accelerated B cell neoplasms in a dose dependent manner, and altered the mutational profile of these neoplasms. Our results illuminate a mechanism through which a low level of IL-10 can create risk of leukemic transformation and support developing evidence that microbial dysbiosis contributes to pediatric B-ALL.

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BLNK suppresses pre–B-cell leukemogenesis through inhibition of JAK3

Blood ◽

10.1182/blood-2008-07-166355 ◽

2009 ◽

Vol 113 (7) ◽

pp. 1483-1492 ◽

Cited By ~ 74

Author(s):

Joji Nakayama ◽

Mutsumi Yamamoto ◽

Katsuhiko Hayashi ◽

Hitoshi Satoh ◽

Kenji Bundo ◽

...

Keyword(s):

Cell Cycle ◽

B Cell ◽

Cell Cycle Arrest ◽

Lymphoblastic Leukemia ◽

Genetic Alterations ◽

Leukemia Cells ◽

Cell Leukemia ◽

Cycle Arrest ◽

B Cell Leukemia

Abstract Pre–B-cell leukemia spontaneously develops in BLNK-deficient mice, and pre–B-cell acute lymphoblastic leukemia cells in children often lack BLNK protein expression, demonstrating that BLNK functions as a tumor suppressor. However, the mechanism by which BLNK suppresses pre–B-cell leukemia, as well as the identification of other genetic alterations that collaborate with BLNK deficiency to cause leukemogenesis, are still unknown. Here, we demonstrate that the JAK3/STAT5 signaling pathway is constitutively activated in pre-B leukemia cells derived from BLNK−/− mice, mostly due to autocrine production of IL-7. Inhibition of IL-7R signaling or JAK3/STAT5 activity resulted in the induction of p27kip1 expression and cell-cycle arrest, accompanied by apoptosis in the leukemia cells. Transgene-derived constitutively active STAT5 (STAT5b-CA) strongly synergized with the loss of BLNK to initiate leukemia in vivo. In the leukemia cells, exogenously expressed BLNK inhibited autocrine JAK3/STAT5 signaling, resulting in p27kip1 induction, cell-cycle arrest, and apoptosis. BLNK-inhibition of JAK3 was dependent on the binding of BLNK to JAK3. These data indicate that BLNK normally regulates IL-7–dependent proliferation and survival of pre–B cells through direct inhibition of JAK3. Thus, somatic loss of BLNK and concomitant mutations leading to constitutive activation of Jak/STAT5 pathway result in the generation of pre–B-cell leukemia.

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Acute lymphoblastic leukemia with Burkitt cell morphology and cytoplasmic immunoglobulin

Blood ◽

10.1182/blood.v56.2.311.311 ◽

1980 ◽

Vol 56 (2) ◽

pp. 311-314 ◽

Cited By ~ 19

Author(s):

DJ Ganick ◽

JL Finlay

Keyword(s):

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Cell Morphology ◽

Lymphoblastic Leukemia ◽

Morphological Characteristics ◽

Cell Leukemia ◽

First Report ◽

Surface Immunoglobulin ◽

B Cell Leukemia

Abstract A case of acute lymphoblastic leukemia with morphological characteristics of Burkitt's leukemia (L3 morphology) is presented. This patient's lymphoblasts were lacking in surface immunoglobulin, but were found to contain cytoplasmic IgM. This is the first report of a morphologically B-cell leukemia showing pre-B-cell characteristics immunologically.

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