PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia

Gu, Zhaohui; Churchman, Michelle L.; Roberts, Kathryn G.; Moore, Ian; Zhou, Xin; Nakitandwe, Joy; Hagiwara, Kohei; Pelletier, S. William; Gingras, Sébastien; Berns, Hartmut; Payne-Turner, Debbie; Hill, Ashley; Iacobucci, Ilaria; Shi, Lei; Pounds, Stanley; Cheng, Cheng; Pei, Deqing; Qu, Chunxu; Newman, Scott; Devidas, Meenakshi; Dai, Yunfeng; Reshmi, Shalini C.; Gastier‐Foster, Julie M.; Raetz, Elizabeth A.; Borowitz, Michael J.; Wood, Brent L.; Carroll, William L.; Zweidler‐McKay, Patrick A.; Rabin, Karen R.; Mattano, Leonard A.; Maloney, Kelly W.; Rambaldi, Alessandro; Spinelli, Orietta; Radich, Jerald P.; Minden, Mark D.; Rowe, Jacob M.; Luger, Selina M.; Litzow, Mark R.; Tallman, Martin S.; Racevskis, Janis; Zhang, Yanming; Bhatia, Ravi; Kohlschmidt, Jessica; Mrózek, Krzysztof; Bloomfield, Clara D.; Stock, Wendy; Kornblau, Steven M.; Kantarjian, Hagop M.; Konopleva, Marina; Evans, Williams E.; Jeha, Sima; Pui, Ching Hon; Yang, Jun J.; Paietta, Elisabeth; Downing, James R.; Relling, Mary V.; Zhang, Jinghui; Loh, Mignon L.; Hunger, Stephen P.; Mullighan, Charles G.

doi:10.1038/s41588-018-0315-5

Cited by 439 publications

(859 citation statements)

References 64 publications

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“…SEM cells infected with the pooled library of sgRNAs were collected at day 0 and day 12 to sequence for sgRNA distribution (Figure 6C). In accordance with prior genome-wide CRISPR screens and functional studies in B-ALL, many survival dependent genes were identified in the top 50 genes in our screen including PAX5 , DOT1L , ZFP64 , YY1 , MEF2C , MYC and KMT2A (26, 29, 50, 51). USF2 was ranked as the top 24 th essential gene in MLLr SEM cells (Figure 6D).…”

Section: Resultssupporting

confidence: 83%

“…As shown by many previous studies, HOXA9 overexpression was observed in refractory MLL-rearranged ALL and AML patients (26–28)(Figures S1A-S1C). Therefore, we utilized our previously reported high-efficiency knock-in strategy, “CHASE knock-in” (29), to deliver the P2A-mCherry cassette upstream of the HOXA9 stop codon in a patient-derived human B-ALL cell line, SEM, which has a typical B-ALL signature along with a t(4;11) translocation and maintains one single allele of the HOXA gene cluster.…”

Section: Resultssupporting

confidence: 78%

“…Taken together, these findings suggest that the USF2/HOXA9 axis plays a role in supporting MLLr B-ALL cell proliferation. In addition, a transcriptome analysis from the largest human B-ALL transcriptome cohort (N=1,988 patients) (26) identified USF2 expression to be significantly correlated with HOXA9 in MLLr-subtype patients (N=136 patients) (Figures 6E-6F and Figure S9A) highlighting that the USF2 and HOXA9 regulation axis could have clinical relevance for patients in this specific subtype.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Functional Interrogation ofHOXA9Regulome in MLLr Leukemia via Reporter-based CRISPR/Cas9 screen

Zhang

Wright

et al. 2020

Preprint

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Aberrant HOXA9 expression is a hallmark of most aggressive acute leukemias, including human acute myeloid leukemia (AML) and subtypes of acute lymphoblastic leukemia (ALL). HOXA9 overexpression not only predicts poor diagnosis and outcome but also plays a critical role in leukemia transformation and maintenance. However, our current understanding of HOXA9 regulation in leukemia is limited, hindering development of therapeutic strategies to treat HOXA9-driven leukemia. To mitigate these challenges, we generated the first HOXA9-mCherry knock-in reporter in an MLL-rearranged (MLLr) B-ALL cell line to dissect HOXA9 regulation. By utilizing the reporter and CRISPR/Cas9 mediated screens, we identified transcription factors controlling HOXA9 expression, including a novel regulator, USF2 and its homolog USF1. USF1/USF2 depletion significantly down-regulated HOXA9 expression and impaired MLLr leukemia cell proliferation. Ectopic expression of HOXA9-MEIS1 fusion protein rescued the impaired leukemia cell proliferation upon USF2 loss. Cut&Run analysis revealed the direct occupancy of USF2 onto HOXA9 promoter in MLLr leukemia cells. Collectively, the HOXA9 reporter facilitated the functional interrogation of the HOXA9 regulome and has advanced our understanding of the molecular regulation network in HOXA9-driven leukemia.

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Section: Resultssupporting

confidence: 83%

Section: Resultssupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Functional Interrogation ofHOXA9Regulome in MLLr Leukemia via Reporter-based CRISPR/Cas9 screen

Zhang

Wright

et al. 2020

Preprint

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“…Although various PAX5 alterations, including fusions, amplifications, or mutations, were detected in BCP-ALL, the expression profiles of these samples were similar regardless of PAX5 alterations without PAX5 deletions. 23 In our cohort, our defined PAX5-altered samples were also clustered into the single cluster, E3, although our sample size was small and our analysis might not be precise. Because PAX5 deleted samples were not necessarily clustered into E3 and were detected in 4 clusters, PAX5 deletion would have different pathogenicity from other PAX5 alterations.…”

Section: Mutation and Copy Number Analysismentioning

confidence: 89%

Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome

et al. 2019

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Children with Down syndrome (DS) are at a 20‐fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non‐DS‐ALL), those with DS and ALL (DS‐ALL) harbor uncommon genetic alterations, suggesting DS‐ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS‐ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS‐ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non‐DS‐ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome‐like subtype, a high‐risk B‐cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS‐ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS‐ALL, but not non‐DS‐ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B‐cell precursors might be associated with increased incidence of B‐cell precursor ALL in DS patients.

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“…In childhood ALL the initiating event occurs most commonly in-utero and consists usually of an aberration of a transcriptional regulator. Progression to leukemia is caused by a series of acquired genetic aberrations that halt B-cell differentiation and increase cell proliferation, survival and self-renewal 2,3 . Increased signaling through RAS or STAT5 pathways are typical progression events and are generally thought to act as the "fuel" enhancing leukemic cell growth [4][5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

An instructive role for IL7RA in the development of human B-cell precursor leukemia

Geron

Savino

Tal

et al. 2020

Preprint

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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is preceded by a clinically silent preleukemia. Experimental models that authentically re-capitulate disease initiation and progression in human cells are lacking. We previously described activating mutations in interleukin 7 receptor alpha (IL7RA) that are associated with the poor-prognosis Philadelphialike (Ph-like) subtype of BCP-ALL. Whether IL7RA signaling has a role in initiation of human BCP-ALL is unknown. IL7RA is essential for mouse B-cell development; however, patients with truncating IL7RA germline mutations develop normal mature B-cell populations. Herein, we explore the consequences of aberrant IL7RA signaling activation in human hematopoietic progenitors on malignant B-cell development. Transplantation of human cord-blood hematopoietic progenitors transduced with activated mutant IL7RA into NOD/LtSz-scid IL2Rγ null mice resulted in B-cell differentiation arrest with aberrant expression of CD34 + and persistence of pro-B cells that survive despite failing to achieve productive rearrangement of immunoglobulin V(D)J gene segments. Activation of IL7RA signaling enhanced self-renewal and facilitated the development of a BCP-ALL in secondary transplanted mice. The development of leukemia was associated with spontaneous acquired deletions in CDKN2A/B and IKZF1 similar to what is observed in Ph-like BCP-ALL in humans. Single cell gene expression analysis suggested that pre-leukemic cells resided within a subpopulation of early B-cell precursors with CD34 + CD10 high CD19 low immunophenotype. The development of a bona fide BCP-ALL from IL7RA transduced cells supports the hypothesis that aberrant activation of the IL7RA pathway in human B-cell lineage progenitors has an instructive role by creating a pre-leukemic state which is vulnerable to transformation. These are the first demonstrations of a role for IL7RA in human B-cell differentiation and of a de-novo Phlike BCP-ALL development from normal human hematopoietic progenitors in vivo.

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PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia

Cited by 439 publications

References 64 publications

Functional Interrogation ofHOXA9Regulome in MLLr Leukemia via Reporter-based CRISPR/Cas9 screen

Functional Interrogation ofHOXA9Regulome in MLLr Leukemia via Reporter-based CRISPR/Cas9 screen

Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome

An instructive role for IL7RA in the development of human B-cell precursor leukemia

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