Table 2.

Oncogenic driver mutations reported in aCML and their functional consequences

Gene (estimated frequency, %)	Mutations	Functional consequences	Disease in animal models	Inhibitors
CALR5,7 (<5)	Frameshift mutation in exon 9	JAK/STAT activation29	Not known	JAK1/2 inhibitors, eg, ruxolitinib, momelotinib
CBL5,30 (10–33)	Missense mutations involving exon 8–9 (in the RING or linker domains); often associated with deletion of second CBL allele or uniparental disomy at 11q2331	Loss of function of E3 ubiquitin ligase that negatively regulates SRC family kinases and receptor tyrosine kinases	Cbl knockout–mild MPN32; knockout of both Cbl and Cbl-b, severe MPN disease33	Src kinase inhibitors, eg, dasatinib, saracatinib, bosutinib, and KX01
CSF3R1,2,4,5 (0–40)	T618I	Constitutive JAK/STAT signaling	Neutrophilic leukemia13	JAK1/2 inhibitors, eg, ruxolitinib, momelitinib
	T615A	Constitutive JAK/STAT signaling	Not tested
	T640N	Constitutive JAK/STAT signaling	Mild neutrophilic leukemia*
	Truncating mutations (frameshift or nonsense) at C-terminus	Modulate cell surface expression and receptor sensitivity to ligand	No evidence of disease*
ETNK134 (9)	N244S, H243Y	Reduced kinase activity and phosphorylation of ethanolamine, a rate-limiting step in phosphatidylethanolamine synthesis	Not known	Not applicable
JAK25 (<5)	V617F	Constitutive JAK/STAT signaling	MPN, gene dosage effects35	JAK1/2 inhibitors, eg, ruxolitinib, momelotinib
KIT40 (6)	D816V (in activation loop)	Constitutive receptor tyrosine kinase signaling	MPN with manipulation of intracellular trafficking of mutant protein36	Dasatinib or PKC412
MPL5 (<5)	W515K, W515L (in juxtamembrane region of thrombopoietin receptor)	Constitutive JAK/STAT signaling	MPN37	JAK1/2 inhibitors, eg, ruxolitinib, momelitinib
RAS4,38 (35–50)	Mutation involving codons 12, 13, or 61	Constitutive MEK/ERK signaling	MPN, CMML, AML39 and others	BRAF or MEK inhibitors

^*Unpublished data from Jeffrey Tyner, May 2015.