Single-cell mutation analysis of clonal evolution in myeloid malignancies.

Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk molecular profiling has suggested that mutations are acquired in a stepwise fashion: mutant genes with high variant allele frequencies appear early in leukaemogenesis, and mutations with lower variant allele frequencies are thought to be acquired later. Although bulk sequencing can provide information about leukaemia biology and prognosis, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity, or definitively elucidate the order of mutations.

Unfolding the Role of Calreticulin in Myeloproliferative Neoplasm Pathogenesis.

In 2013, two seminal studies identified gain-of-function mutations in the Calreticulin () gene in a subset of /-negative myeloproliferative neoplasm (MPN) patients. CALR is an endoplasmic reticulum (ER) chaperone protein that normally binds misfolded proteins in the ER and prevents their export to the Golgi and had never previously been reported mutated in cancer or to be associated with hematologic disorders. Further investigation determined that mutated is able to achieve oncogenic transformation primarily through constitutive activation of the MPL-JAK-STAT signaling axis.

Targeting the CALR interactome in myeloproliferative neoplasms.

Mutations in the ER chaperone calreticulin (CALR) are common in myeloproliferative neoplasm (MPN) patients, activate the thrombopoietin receptor (MPL), and mediate constitutive JAK/STAT signaling. The mechanisms by which CALR mutations cause myeloid transformation are incompletely defined. We used mass spectrometry proteomics to identify CALR-mutant interacting proteins.

Genetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis.

Genetic studies have identified recurrent somatic mutations in acute myeloid leukemia (AML) patients, including in the Wilms' tumor 1 () gene. The molecular mechanisms by which mutations contribute to leukemogenesis have not yet been fully elucidated. We investigated the role of gene dosage in steady-state and pathologic hematopoiesis.