**Table 3.**

*Acute Leukemias*

**Genetic subtype**

1- *NF1* mutated JMML:

2- *PTPN11* mutated JMML:

3- *NRAS*mutated JMML:

4- *KRAS*mutated JMML:

5- *CBL*mutated JMML:

**Characteristics:**

• **Incidence: 5–10% of cases.** • **Higher platelet count.**

**successfully be performed.**

**compared with other subtypes.**

**children with high levels of HbF).**

**a normal or only slightly elevated HbF.**

**present with particularly severe disease.** • **Monosomy 7 is frequently noted in leukemic cells.**

• *KRAS***-mutated JMML shares many features with RALD.**

• **Frequent acquisition of** *NF1* **haploinsufficiency.**

• **Incidence: 35% of cases.**

• **Incidence: 18% of cases.** • **A heterogeneous course.**

• **Incidence: 14% of cases.**

• **Incidence: 12 to 18% of cases.**

**etic cells.**

**intervention.**

**allogeneic HSCT.**

*Clincal features of genetic subtypes of JMML.*

**NF-1, NS, and Legius syndrome.**

• **The value of allogeneic HSCT is uncertain.**

**is located. No other concomitant mutations are found.**

• **Higher percentage of blasts in bone marrow.**

• **More often diagnosed after the age of 5 years than other subtypes.**

• **Although some of the younger children can initially enjoy a relatively unaffected clinical course,** *NF1***-mutated JMML is invariably fatal unless allogeneic HSCT can** 

• **A rapidly fatal disorder unless allogeneic HSCT can successfully be performed.** • **Significantly worse outcome with higher probability of relapse rates when** 

• **The p.(Glu76Lys) is the most frequently observed** *PTPN11* **finding in JMML.**

• **A considerable percentage of patients relapse after HSCT (typically older** 

• **Some patients enjoy an indolent course with spontaneous regression (typically infants or cases with G12S mutation). Clinically, these children are well and show** 

• **Most children are diagnosed below the age of 1 year (i.e, infants). They often** 

• **In some cases, an impressive treatment response to azacitidine has been observed.** • **Although Aggressive at presentation,** *KRAS***-mutated JMML has a low relapse rate after allogeneic HSCT and may benefit from less intensive preparative regimens.**

• **Patients display several congenital anomalies that overlap with those observed in** 

• **Self-limiting disease: most children experience spontaneous regression of their myeloproliferation despite the persistence of LOH of the CBL locus in hematopoi-**

• **Observation without therapeutic intervention is generally advised, but in some instances grossly enlarged spleens and thrombocytopenia require therapeutic** 

• **Frequent occurrence of partial rejection with stable mixed chimerism after** 

• **The only recurrent variant is copy-neutral isodisomy (LOH) at 11q23.3 where CBL** 

**26**

**Table 2.**

*Poor prognostic factors.*

more somatic mutations at diagnosis have significantly worse event-free and overall survival rates than those with one or no event. In harmony with these findings, the known clinical risk factors predictive of poor outcome (**Table 3**) are only weakly associated with the type of index mutation but they would rather fit patients with two or more underlying somatic mutations.

In addition to the mutations in RAS pathway genes (*PTPN11, NRAS, KRAS, CBL, or NF1*), other driver mutations thought to be the initiating events of JMML have been recently identified such as *RRAS, RRAS2*, or *SH2B3* mutations. *RRAS* and *RRAS2* genes are both members of the RAS GTPase family and hence expanded the spectrum of RAS pathway mutations in JMML. Activating mutations in *RRAS* underlie a phenotype within the RASopathy spectrum. Children with *RRAS*mutated JMML can have an atypical clinical course with rapid progression to AML [22]. Somatic *RRAS* mutations co-occurred with acquired *NRAS* lesions in atypical JMML characterized by late onset and rapid progression to AML as well.

#### **7. Secondary genetic mutations in JMML**

In addition to the initiating canonical RAS pathway mutations, secondary clonal abnormalities were detected in about one-half of the patients. The importance of these mutations relies in how secondary mutations alter the behavior of cells in contrast to cells harboring only the primary lesion. Secondary mutations are often subclonal and may be involved in disease progression rather than initiation of leukemia. It appears that such mutations characterize patients with the highest risk of progression and poor outcome. The acquisition of the second mutation would thus also explain the continuum between RALD and leukemia. The clone harboring the secondary event frequently expands at the time of relapse post HSCT. This phenomenon has important therapeutic implications. Combination of therapies with agents that target the RAS pathway as well as the secondary genetic event could prove more efficacious in the correct genetic context than monotherapy alone.

The secondary mutational events occur inside or outside the canonical RAS pathway axis. They include second hits targeting the RAS pathway (so-called 'RAS double mutants') as well as mutations in *SETBP1, JAK3, SH283*, components of the polycomb repressive complex 2 (like *EZH2* and A*SXL1*), and occasionally, spliceosome genes. Some authors linked differential expression of key regulatory noncoding RNAs, such as let-7100 or miR-150-5p,101 to the various genetic subgroups

of JMML [23]. Secondary mutations of *SETBP1* and *JAK3* were the most frequent mutations (around 15% of children) and were presumed to be involved in tumor progression and poor clinical outcomes.
